instruction stringlengths 353 426 | output stringlengths 1.03k 1.36k | enhanced_prompt stringlengths 730 2.79k | enhanced_completion stringlengths 1.99k 6.44k | accession stringlengths 12 12 | cadd_phred float64 23.4 36 | clingen_validity stringclasses 1
value | clinvar_id int64 12.6k 4.85M | condition_match_type stringclasses 2
values | gene stringclasses 10
values | investigation_score int64 8 14 | investigation_tier stringclasses 1
value | n_concordant int64 2 5 | omim_primary stringclasses 10
values | original_context stringlengths 186 261 | primary_condition stringclasses 5
values | protein_change stringlengths 9 29 | record_id stringlengths 12 12 | reference_doi stringclasses 1
value | reference_pmid stringclasses 1
value | snapshot_date timestamp[s]date 2026-06-28 00:00:00 2026-06-28 00:00:00 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Cys142Arg
ClinVar ID: 3338730
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and state... | The ENSP00000302486.5:p.Cys142Arg variant (ClinVar ID: 3338730) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: VUS Reclassification Analysis
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity. Specifically:
1. **Evidence Summary**: Detail the computational evidence and gene–disease validity context using ClinGen and GenCC standards.... | # Variant Prioritization and Evidence Analysis Report
**Date of Analysis:** June 30, 2026
**Variant Identification:** MAP2K1 ENSP00000302486.5:p.Cys142Arg
**ClinVar Accession:** 3338730 (VCV003338730)
**Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615279)
**Prioritization Tier:** Tier 1 (Highes... | VCV003338730 | 33 | Definitive | 3,338,730 | broader_clingen_entity | MAP2K1 | 13 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3338730
VCV003338730
ENSP00000302486.5:p.Cys142Arg
13
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
2cf0855ca9d6 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Cys142Arg | 2cf0855ca9d6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Asn134Ile
ClinVar ID: 3633616
Investigation score: 11
CADD PHRED: 30.0
Concordant predictors: 5
Include the ClinGen and GenCC validity context and state w... | The ENSP00000357306.3:p.Asn134Ile variant (ClinVar ID: 3633616) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 30.0, and support from 5 concordant computational predictor(s). Additional... | # Task: Clinical Variant Evidence Summary
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity. Specifically, incorporate context from ClinGen (Clinical Genome Resource) and GenCC (Gene Curation Coalition) regarding validity. Conclude... | # Clinical Variant Evidence Summary
### 1. Computational Evidence Level
The variant RIT1 p.Asn134Ile (ClinVar 3633616) is categorized as **Tier 1 — highest priority** for investigation. The computational metrics provided are:
* **Investigation Score**: 11
* **CADD PHRED Score**: 30.0
* **Concordant Predictor Cou... | VCV003633616 | 30 | Definitive | 3,633,616 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 5 | 615355 | RIT1
3633616
VCV003633616
ENSP00000357306.3:p.Asn134Ile
11
Tier 1 — highest priority
30.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6fbe32f69775 | Noonan syndrome | ENSP00000357306.3:p.Asn134Ile | 6fbe32f69775 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: PTPN11
Protein variant: ENSP00000340944.3:p.Gly503Arg
ClinVar ID: 40559
Investigation score: 14
CADD PHRED: 33.0
Concordant predictors: 4
Contextualize the gene–disease relationship ac... | The ENSP00000340944.3:p.Gly503Arg variant (ClinVar ID: 40559) in PTPN11 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Computational Prioritization Analysis for Genetic Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation. Specifically:
1. **Data Review**: Examine the variant's investigation score, CADD PHRED score, and concordant pr... | # Computational Prioritization Analysis: PTPN11 p.Gly503Arg
## Variant Identification
* **Gene:** PTPN11
* **Protein Variant:** ENSP00000340944.3:p.Gly503Arg
* **ClinVar ID:** 40559 (VCV000040559)
## Computational Evidence Review
The candidate variant exhibits the following computational metrics, representing in sili... | VCV000040559 | 33 | Definitive | 40,559 | exact | PTPN11 | 14 | Tier 1 — highest priority | 4 | 176876 | PTPN11
40559
VCV000040559
ENSP00000340944.3:p.Gly503Arg
14
Tier 1 — highest priority
33.0
4
Noonan syndrome with multiple lentigines
Definitive
exact
176876
40496714
10.1016/j.gimo.2025.103430
2026-06-28
0763cb6b21c6 | Noonan syndrome with multiple lentigines | ENSP00000340944.3:p.Gly503Arg | 0763cb6b21c6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Ala77Thr
ClinVar ID: 183403
Investigation score: 11
CADD PHRED: 28.9
Concordant predictors: 4
Contextualize the gene–disease relationship acco... | The ENSP00000357306.3:p.Ala77Thr variant (ClinVar ID: 183403) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 28.9, and support from 4 concordant computational predictor(s). Additional p... | # Task: Computational Prioritization Analysis for Gene Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
## Instructions
1. **Data Analysis**: Review the variant metrics including the investigation score, CADD PHRED sco... | # Computational Prioritization Analysis: RIT1 Variant
## Variant Identification
* **Gene:** RIT1
* **Protein Variant:** ENSP00000357306.3:p.Ala77Thr
* **ClinVar ID:** 183403
* **Associated Condition:** Noonan syndrome (OMIM: 615355)
## Computational Evidence Metrics
The following computational values are reported exa... | VCV000183403 | 28.9 | Definitive | 183,403 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 4 | 615355 | RIT1
183403
VCV000183403
ENSP00000357306.3:p.Ala77Thr
11
Tier 1 — highest priority
28.9
4
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
65c731a51da7 | Noonan syndrome | ENSP00000357306.3:p.Ala77Thr | 65c731a51da7 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Glu501Lys
ClinVar ID: 13977
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context an... | The ENSP00000493543.1:p.Glu501Lys variant (ClinVar ID: 13977) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: Tier 1 Prioritization Analysis for Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, describe the Tier 1 prioritization of this Variant of Uncertain Significance (VUS).
**Requirements:**
1. **Analysis**: Evaluate the variant using the provided metrics (I... | # Tier 1 Prioritization Analysis: BRAF p.Glu501Lys
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Glu501Lys
* **ClinVar ID:** 13977
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## Computational Evidence
The prioritization of this variant is based on t... | VCV000013977 | 32 | Definitive | 13,977 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
13977
VCV000013977
ENSP00000493543.1:p.Glu501Lys
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
cec7afdae4e6 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Glu501Lys | cec7afdae4e6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Gly135Val
ClinVar ID: 3061850
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship ... | The ENSP00000262948.4:p.Gly135Val variant (ClinVar ID: 3061850) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | Analyze the provided computational prioritization data for the selected gene variant candidate. Specifically:
1. **Data Review**: Examine the variant's metrics, including the Investigation score, CADD PHRED score, and number of concordant predictors.
2. **Contextual Analysis**: Contextualize the gene–disease relations... | ### Variant Prioritization Analysis: MAP2K2 ENSP00000262948.4:p.Gly135Val
#### 1. Computational Evidence Review
The variant MAP2K2 ENSP00000262948.4:p.Gly135Val (ClinVar ID: 3061850) exhibits the following computational metrics:
* **Investigation Score:** 12
* **CADD PHRED Score:** 32.0
* **Concordant Predictors... | VCV003061850 | 32 | Definitive | 3,061,850 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
3061850
VCV003061850
ENSP00000262948.4:p.Gly135Val
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
7d6db66db411 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Gly135Val | 7d6db66db411 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Pro266Arg
ClinVar ID: 3636796
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational p... | The ENSP00000262948.4:p.Pro266Arg variant (ClinVar ID: 3636796) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity associated with the provided Variant of Uncertain Significance (VUS) classified as Tier 1.
**Important Clarification:** Clearly explain that "Tier 1" represents a computational... | ### Computational Evidence Summary for MAP2K2 Variant (ClinVar ID: 3636796)
**Variant Identification**
* **Gene:** *MAP2K2*
* **Protein Change:** p.Pro266Arg (ENSP00000262948.4)
* **ClinVar Accession:** VCV003636796
* **Current Classification:** Variant of Uncertain Significance (VUS)
**Computational Metrics*... | VCV003636796 | 33 | Definitive | 3,636,796 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
3636796
VCV003636796
ENSP00000262948.4:p.Pro266Arg
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
33e7b63ddde0 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Pro266Arg | 33e7b63ddde0 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Leu525Gln
ClinVar ID: 520890
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context a... | The ENSP00000493543.1:p.Leu525Gln variant (ClinVar ID: 520890) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional ... | # Task: Tier 1 Prioritization Analysis for Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, perform the following:
1. **Describe the Tier 1 Prioritization**: Analyze the variant's priority status using the provided metrics.
2. **Contextualize Validity**: Incorpo... | # Tier 1 Prioritization Analysis: BRAF p.Leu525Gln (ClinVar 520890)
## 1. Tier 1 Prioritization Description
The variant BRAF ENSP00000493543.1:p.Leu525Gln (ClinVar ID: 520890) has been assigned a **Tier 1 — highest priority** status for computational investigation. This prioritization reflects a convergence of high-sc... | VCV000520890 | 32 | Definitive | 520,890 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
520890
VCV000520890
ENSP00000493543.1:p.Leu525Gln
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
25b4759eab5a | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Leu525Gln | 25b4759eab5a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly466Arg
ClinVar ID: 44801
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Clarify which additional evidence, including func... | The ENSP00000493543.1:p.Gly466Arg variant (ClinVar ID: 44801) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following actions:
1. **Describe the Tier 1 Prioritization**: Analyze the Variant of Uncertain Significance (VUS) using the provided metrics (Investigation score, CADD PHRED, co... | # VUS Tier 1 Prioritization and Reclassification Analysis
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Gly466Arg
* **ClinVar ID:** 44801 (VCV000044801)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## 1. Tier 1 Prioritization Analysis
The var... | VCV000044801 | 32 | Definitive | 44,801 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
44801
VCV000044801
ENSP00000493543.1:p.Gly466Arg
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
68f743327f3a | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly466Arg | 68f743327f3a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Leu184Pro
ClinVar ID: 2086788
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000262948.4:p.Leu184Pro variant (ClinVar ID: 2086788) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority for the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
**Required Analysis:**
1. Evaluate the provided variant data.
2. Integrate ClinGen (Clinical Genome Resource) ... | # Clinical Investigation Priority Assessment
**Investigation Priority Statement**
The variant MAP2K2 p.Leu184Pro (ClinVar ID: 2086788) is assigned a **Tier 1 — highest priority** status within the unified RASopathy VUS Series pipeline. This designation indicates an elevated priority for further clinical investigation ... | VCV002086788 | 32 | Definitive | 2,086,788 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
2086788
VCV002086788
ENSP00000262948.4:p.Leu184Pro
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
faeeeb495518 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Leu184Pro | faeeeb495518 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Leu194Phe
ClinVar ID: 2724657
Investigation score: 12
CADD PHRED: 31.0
Concordant predictors: 5
Contextualize the gene–disease relationship ac... | The ENSP00000358464.5:p.Leu194Phe variant (ClinVar ID: 2724657) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additiona... | # Task: Tier 1 Prioritization Analysis for Variant of Uncertain Significance (VUS)
## Instructions
Based on the computational criteria and contextual data provided below, generate a detailed description of the **Tier 1 prioritization** for the specified Variant of Uncertain Significance (VUS).
Your response must:
1.... | # Tier 1 Prioritization Analysis: SHOC2 p.Leu194Phe
## Variant Identification
* **Gene:** SHOC2
* **Protein Variant:** ENSP00000358464.5:p.Leu194Phe
* **ClinVar ID:** 2724657 (VCV002724657)
* **Associated Condition:** Noonan syndrome-like disorder with loose anagen hair (OMIM: 607721)
## 1. Analysis of Comput... | VCV002724657 | 31 | Definitive | 2,724,657 | broader_clingen_entity | SHOC2 | 12 | Tier 1 — highest priority | 5 | 607721 | SHOC2
2724657
VCV002724657
ENSP00000358464.5:p.Leu194Phe
12
Tier 1 — highest priority
31.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
a6db36e43218 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Leu194Phe | a6db36e43218 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Ala77Gly
ClinVar ID: 850519
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computational prior... | The ENSP00000357306.3:p.Ala77Gly variant (ClinVar ID: 850519) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additional p... | You are an expert clinical genetics analyst. Your task is to summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) detailed in the data block below.
**Definitions:**
- **VUS (Variant of Uncertain Significance):** A genetic change where the effect on healt... | **Variant Prioritization Summary: RIT1 c.[Variant] p.Ala77Gly**
**Variant Identification**
* **Gene:** *RIT1*
* **Protein Change:** ENSP00000357306.3:p.Ala77Gly
* **ClinVar Accession:** VCV000850519 (ClinVar ID: 850519)
* **Associated Condition:** Noonan syndrome (OMIM #615355)
* **Current Classification:** ... | VCV000850519 | 32 | Definitive | 850,519 | broader_clingen_entity | RIT1 | 12 | Tier 1 — highest priority | 5 | 615355 | RIT1
850519
VCV000850519
ENSP00000357306.3:p.Ala77Gly
12
Tier 1 — highest priority
32.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
17d8cdfd48de | Noonan syndrome | ENSP00000357306.3:p.Ala77Gly | 17d8cdfd48de | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Ser637Leu
ClinVar ID: 2123228
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational pri... | The ENSP00000493543.1:p.Ser637Leu variant (ClinVar ID: 2123228) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) detailed below.
**Key Clarification**: Explicitly state that "Tier 1" represents a high computational priority for review, not a... | ### Computational Evidence Summary for BRAF c.1910C>T (p.Ser637Leu)
**Variant Identification**
* **Gene:** *BRAF*
* **Protein Change:** ENSP00000493543.1:p.Ser637Leu
* **ClinVar Variation ID:** 2123228 (VCV002123228)
* **Current Classification:** Variant of Uncertain Significance (VUS)
#### 1. Computational E... | VCV002123228 | 33 | Definitive | 2,123,228 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
2123228
VCV002123228
ENSP00000493543.1:p.Ser637Leu
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d26aefb37d36 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Ser637Leu | d26aefb37d36 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Arg193Gln
ClinVar ID: 179899
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including f... | The ENSP00000262948.4:p.Arg193Gln variant (ClinVar ID: 179899) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additiona... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following two tasks regarding the Variant of Uncertain Significance (VUS):
1. **Describe the Tier 1 Prioritization**: Explain why this variant is classified as "Tier 1 — highest... | **Variant Identification**
* **Gene:** MAP2K2
* **Protein Change:** ENSP00000262948.4:p.Arg193Gln
* **ClinVar ID:** 179899
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615280)
### 1. Tier 1 Prioritization Rationale
The classification of MAP2K2 p.Arg193Gln as "Tier 1 — highest priority" for... | VCV000179899 | 33 | Definitive | 179,899 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
179899
VCV000179899
ENSP00000262948.4:p.Arg193Gln
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
9ffc4d5f276b | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Arg193Gln | 9ffc4d5f276b | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly469Glu
ClinVar ID: 13974
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship accordi... | The ENSP00000493543.1:p.Gly469Glu variant (ClinVar ID: 13974) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Instructions
1. **Priority Assessment**: Evaluate the variant's priority based on ... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** *BRAF*
* **Protein Variant:** ENSP00000493543.1:p.Gly469Glu
* **ClinVar ID:** 13974
## 1. Priority Assessment
Based on the provided metrics, this variant is assigned **Tier 1 — highest priority** for clinical investigation. The computa... | VCV000013974 | 32 | Definitive | 13,974 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
13974
VCV000013974
ENSP00000493543.1:p.Gly469Glu
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b52e4a9354b6 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly469Glu | b52e4a9354b6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Ser231Trp
ClinVar ID: 2846662
Investigation score: 14
CADD PHRED: 36.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a comput... | The ENSP00000302486.5:p.Ser231Trp variant (ClinVar ID: 2846662) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 36.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
**Critical Requirement:** Clearly explain that "Tier 1" represents a computational priority for further r... | ### Clinical Investigation Priority Assessment: MAP2K1 c.[Variant] p.Ser231Trp
**Variant Identification**
* **Gene:** *MAP2K1*
* **Protein Change:** p.Ser231Trp (ENSP00000302486.5)
* **ClinVar Variation ID:** 2846662 (VCV002846662)
* **Associated Condition:** Cardiofaciocutaneous Syndrome (CFC)
#### 1. Comput... | VCV002846662 | 36 | Definitive | 2,846,662 | broader_clingen_entity | MAP2K1 | 14 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
2846662
VCV002846662
ENSP00000302486.5:p.Ser231Trp
14
Tier 1 — highest priority
36.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b2669264a613 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Ser231Trp | b2669264a613 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Gly93Val
ClinVar ID: 4614843
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 5
Contextualize the gene–disease relationship acco... | The ENSP00000357306.3:p.Gly93Val variant (ClinVar ID: 4614843) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additional ... | # Task: VUS Tier 1 Prioritization and Gene-Disease Contextualization
Based on the computational criteria and raw data provided below, perform the following analysis for the Variant of Uncertain Significance (VUS):
1. **Tier 1 Prioritization Description**: Describe the prioritization of this variant as "Tier 1 — highe... | ### Variant Prioritization and Gene-Disease Contextualization Report
**Variant Identification**
* **Gene:** RIT1
* **Protein Variant:** ENSP00000357306.3:p.Gly93Val
* **ClinVar ID:** 4614843 (VCV004614843)
* **Associated Condition:** Noonan syndrome
**1. Tier 1 Prioritization Description**
Based on the provided compu... | VCV004614843 | 32 | Definitive | 4,614,843 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 5 | 615355 | RIT1
4614843
VCV004614843
ENSP00000357306.3:p.Gly93Val
11
Tier 1 — highest priority
32.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
976b4bf56458 | Noonan syndrome | ENSP00000357306.3:p.Gly93Val | 976b4bf56458 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Asn271Ser
ClinVar ID: 4076674
Investigation score: 12
CADD PHRED: 27.9
Concordant predictors: 5
Contextualize the gene–disease relationship a... | The ENSP00000358464.5:p.Asn271Ser variant (ClinVar ID: 4076674) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 27.9, and support from 5 concordant computational predictor(s). Additiona... | # Task: Analyze Computational Prioritization Data for Genetic Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation. Specifically:
1. **Data Review**: Examine the variant's metrics, including the investigation score, CADD PHR... | ### Computational Prioritization Analysis: SHOC2 p.Asn271Ser
**1. Computational Evidence Review**
The candidate variant **SHOC2 ENSP00000358464.5:p.Asn271Ser** (ClinVar ID: 4076674) has been assigned the following computational metrics, reported exactly as provided:
* **Investigation Score:** 12
* **CADD PHRED Sco... | VCV004076674 | 27.9 | Definitive | 4,076,674 | broader_clingen_entity | SHOC2 | 12 | Tier 1 — highest priority | 5 | 607721 | SHOC2
4076674
VCV004076674
ENSP00000358464.5:p.Asn271Ser
12
Tier 1 — highest priority
27.9
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
574b6cc9373a | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Asn271Ser | 574b6cc9373a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: RAF1
Protein variant: ENSP00000251849.4:p.Phe360Ser
ClinVar ID: 981541
Investigation score: 13
CADD PHRED: 34.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000251849.4:p.Phe360Ser variant (ClinVar ID: 981541) in RAF1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 34.0, and support from 4 concordant computational predictor(s). Additional ... | # Task: Computational Prioritization Analysis for RAF1 Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
## Objectives
1. **Contextual Analysis**: Integrate ClinGen (Clinical Genome Resource) and GenCC (Gene Curation Co... | # Computational Prioritization Analysis: RAF1 p.Phe360Ser
## Variant Identification
* **Gene:** RAF1 (HGNC:9829)
* **Protein Variant:** ENSP00000251849.4:p.Phe360Ser
* **ClinVar Accession:** 981541 (VCV000981541)
* **Associated Condition:** Noonan syndrome (OMIM: 611553)
## Computational Evidence Reporting
The follow... | VCV000981541 | 34 | Definitive | 981,541 | exact | RAF1 | 13 | Tier 1 — highest priority | 4 | 611553 | RAF1
981541
VCV000981541
ENSP00000251849.4:p.Phe360Ser
13
Tier 1 — highest priority
34.0
4
Noonan syndrome
Definitive
exact
611553
40496714
10.1016/j.gimo.2025.103430
2026-06-28
f86e148a01d9 | Noonan syndrome | ENSP00000251849.4:p.Phe360Ser | f86e148a01d9 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Gly210Arg
ClinVar ID: 1316067
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a comp... | The ENSP00000302486.5:p.Gly210Arg variant (ClinVar ID: 1316067) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | Based on the computational criteria provided below, describe the Tier 1 prioritization for the specified Variant of Uncertain Significance (VUS).
**Definitions:**
- **VUS (Variant of Uncertain Significance):** A genetic change whose impact on health is not yet known.
- **Tier 1:** Indicates the highest computational ... | ### Tier 1 Computational Prioritization Analysis: MAP2K1 c.[Variant] p.Gly210Arg
**Variant Identification**
* **Gene:** *MAP2K1*
* **Protein Change:** p.Gly210Arg (ENSP00000302486.5)
* **ClinVar Accession:** VCV001316067 (Variation ID: 1316067)
* **Associated Condition:** Cardiofaciocutaneous syndrome (CFC)
#... | VCV001316067 | 33 | Definitive | 1,316,067 | broader_clingen_entity | MAP2K1 | 13 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
1316067
VCV001316067
ENSP00000302486.5:p.Gly210Arg
13
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
56e5a010eb22 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Gly210Arg | 56e5a010eb22 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Phe464Ser
ClinVar ID: 981564
Investigation score: 14
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational prio... | The ENSP00000384675.2:p.Phe464Ser variant (ClinVar ID: 981564) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional ... | # Task: Analyze Computational Evidence and Gene-Disease Validity for a Tier 1 VUS
Please summarize the computational evidence level and gene–disease validity associated with the Variant of Uncertain Significance (VUS) detailed below.
**Important Clarification:** Explicitly state that "Tier 1" represents a computatio... | ### Computational Evidence Summary for SOS1 c.[Variant] p.Phe464Ser (VCV000981564)
**Computational Metrics Analysis**
The variant ENSP00000384675.2:p.Phe464Ser in the *SOS1* gene is associated with the following computational evidence values derived from the provided input data:
* **CADD PHRED Score:** 33.0. This va... | VCV000981564 | 33 | Definitive | 981,564 | exact | SOS1 | 14 | Tier 1 — highest priority | 4 | 163950 | SOS1
981564
VCV000981564
ENSP00000384675.2:p.Phe464Ser
14
Tier 1 — highest priority
33.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
47b23096d789 | Noonan syndrome | ENSP00000384675.2:p.Phe464Ser | 47b23096d789 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: SOS2
Protein variant: ENSP00000216373.5:p.Val336Asp
ClinVar ID: 4709552
Investigation score: 11
CADD PHRED: 27.1
Concordant predictors: 5
Contextualize the gene–disease relationship according to C... | The ENSP00000216373.5:p.Val336Asp variant (ClinVar ID: 4709552) in SOS2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 27.1, and support from 5 concordant computational predictor(s). Additional... | Summarize the computational evidence level and gene–disease validity for the following Tier 1 Variant of Uncertain Significance (VUS). Additionally, contextualize the gene–disease relationship according to ClinGen standards, explicitly noting any differences in disease-entity specificity or MONDO (Monarch Disease Ontol... | **Variant Identification**
* **Gene:** *SOS2*
* **Protein Change:** ENSP00000216373.5:p.Val336Asp
* **ClinVar Variation ID:** 4709552 (VCV004709552)
* **Current Classification:** Variant of Uncertain Significance (VUS)
* **Prioritization Tier:** Tier 1 (Highest Computational Priority)
**Computational Evidence Assessme... | VCV004709552 | 27.1 | Definitive | 4,709,552 | broader_clingen_entity | SOS2 | 11 | Tier 1 — highest priority | 5 | 616559 | SOS2
4709552
VCV004709552
ENSP00000216373.5:p.Val336Asp
11
Tier 1 — highest priority
27.1
5
Noonan syndrome
Definitive
broader_clingen_entity
616559
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6168fabbf1d3 | Noonan syndrome | ENSP00000216373.5:p.Val336Asp | 6168fabbf1d3 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Arg497Pro
ClinVar ID: 934560
Investigation score: 14
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and... | The ENSP00000384675.2:p.Arg497Pro variant (ClinVar ID: 934560) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional ... | # Clinical Investigation Priority Assessment
Evaluate the clinical investigation priority for the following Variant of Uncertain Significance (VUS) identified by the unified RASopathy pipeline.
**Definitions:**
- **VUS**: Variant of Uncertain Significance.
- **ACMG/AMP**: American College of Medical Genetics and Gen... | # Clinical Investigation Priority Assessment
**Variant:** *SOS1* ENSP00000384675.2:p.Arg497Pro (ClinVar ID: 934560)
**Phenotype:** Noonan syndrome
## 1. Contextual Validation
The gene–disease relationship between *SOS1* and Noonan syndrome is classified as **Definitive** by ClinGen GCEP, with an **exact** condition ... | VCV000934560 | 33 | Definitive | 934,560 | exact | SOS1 | 14 | Tier 1 — highest priority | 4 | 163950 | SOS1
934560
VCV000934560
ENSP00000384675.2:p.Arg497Pro
14
Tier 1 — highest priority
33.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
add8d73541c9 | Noonan syndrome | ENSP00000384675.2:p.Arg497Pro | add8d73541c9 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: HRAS
Protein variant: p.Gly13Val
ClinVar ID: 180848
Investigation score: 8
CADD PHRED: 23.4
Concordant predictors: 3
Clarify which additional evidence, including functional studies, segregation da... | The p.Gly13Val variant (ClinVar ID: 180848) in HRAS was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 8, a CADD PHRED score of 23.4, and support from 3 concordant computational predictor(s). Additional pipeline evidence: l... | # Task: Genetic Variant Evidence Analysis
You are an expert genetic counselor and clinical genomicist. Analyze the provided Variant of Uncertain Significance (VUS) data to evaluate its current classification and identify requirements for reclassification.
## Instructions
1. **Evidence Summary**: Based on the data be... | # Genetic Variant Evidence Analysis
**Variant:** *HRAS* c.38G>T (p.Gly13Val)
**ClinVar ID:** 180848 (VCV000180848)
## 1. Evidence Summary
### Computational Evidence
The current computational assessment for this variant is based on the following in silico metrics provided in the investigation data:
* **CADD PHRED... | VCV000180848 | 23.4 | Definitive | 180,848 | exact | HRAS | 8 | Tier 1 — highest priority | 3 | 218040 | HRAS
180848
VCV000180848
p.Gly13Val
8
Tier 1 — highest priority
23.4
3
Costello syndrome
Definitive
exact
218040
40496714
10.1016/j.gimo.2025.103430
2026-06-28
3128c77ceb69 | Costello syndrome | p.Gly13Val | 3128c77ceb69 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Gly80Ser
ClinVar ID: 1440001
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including ... | The ENSP00000302486.5:p.Gly80Ser variant (ClinVar ID: 1440001) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additiona... | # Task: Analyze Computational Prioritization Data for Genetic Variant Reclassification
You are an expert geneticist and variant curator. Analyze the provided computational prioritization data for a specific gene variant selected as a candidate for additional functional investigation. Based on this data, clarify exactl... | ### Variant Prioritization Analysis: MAP2K1 p.Gly80Ser
**Variant Identification and Computational Metrics**
The variant under review is **MAP2K1 p.Gly80Ser** (ENSP00000302486.5:p.Gly80Ser; ClinVar ID: 1440001; VCV: VCV001440001). The following computational prioritization metrics have been recorded for this candidate:... | VCV001440001 | 33 | Definitive | 1,440,001 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
1440001
VCV001440001
ENSP00000302486.5:p.Gly80Ser
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
0c47e324ecb6 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Gly80Ser | 0c47e324ecb6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly596Val
ClinVar ID: 40387
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship accor... | The ENSP00000493543.1:p.Gly596Val variant (ClinVar ID: 40387) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: Tier 1 Prioritization Analysis for Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, describe the Tier 1 prioritization for the specified variant.
## Instructions
1. **Prioritization Description**: Analyze the provided metrics (Investigation score, CADD ... | # Tier 1 Prioritization Analysis: BRAF p.Gly596Val
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Gly596Val
* **ClinVar ID:** 40387 (VCV000040387)
* **Associated Condition:** Cardiofaciocutaneous syndrome
## Computational Prioritization Metrics
The variant has been assigned a **... | VCV000040387 | 32 | Definitive | 40,387 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
40387
VCV000040387
ENSP00000493543.1:p.Gly596Val
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
7cfc072f6aef | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly596Val | 7cfc072f6aef | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Leu325Arg
ClinVar ID: 3902878
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Clarify which additional evidence, including functional ... | The ENSP00000302486.5:p.Leu325Arg variant (ClinVar ID: 3902878) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Genetic Variant Analysis and Reclassification Roadmap
You are an expert clinical geneticist and variant curator. Analyze the provided data for a Tier 1 Variant of Uncertain Significance (VUS) to summarize its current evidence level and define the path to reclassification.
## Definitions
- **VUS**: Variant of ... | ### Variant Analysis Report: MAP2K1 p.Leu325Arg
## 1. Variant Identification
* **Gene:** MAP2K1
* **Protein Change:** ENSP00000302486.5:p.Leu325Arg
* **ClinVar Identification:** 3902878 (VCV003902878)
* **Current Classification:** Variant of Uncertain Significance (VUS)
* **Prioritization Tier:** Tier 1 (Highest Prior... | VCV003902878 | 31 | Definitive | 3,902,878 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3902878
VCV003902878
ENSP00000302486.5:p.Leu325Arg
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
cdc006f168df | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Leu325Arg | cdc006f168df | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Asn581Ile
ClinVar ID: 2795673
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Contextualize the gene–disease relationship acc... | The ENSP00000493543.1:p.Asn581Ile variant (ClinVar ID: 2795673) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization and Gene-Disease Contextualization
Based on the computational criteria and raw data provided below, perform the following analysis for the specified Variant of Uncertain Significance (VUS):
1. **Tier 1 Prioritization Description**: Describe the rationale for prioritizing this variant... | ### Variant Prioritization Analysis: BRAF p.Asn581Ile
**1. Tier 1 Prioritization Description**
The variant BRAF p.Asn581Ile (ClinVar ID: 2795673) has been assigned a Tier 1 prioritization status, indicating the highest priority for computational investigation. This designation is driven by the following quantitative ... | VCV002795673 | 33 | Definitive | 2,795,673 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
2795673
VCV002795673
ENSP00000493543.1:p.Asn581Ile
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d2e7c6d62b04 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Asn581Ile | d2e7c6d62b04 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Glu81Gly
ClinVar ID: 183405
Investigation score: 14
CADD PHRED: 32.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computatio... | The ENSP00000357306.3:p.Glu81Gly variant (ClinVar ID: 183405) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additional p... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
**Critical Clarification:** Clearly explain that a "Tier 1" classification represents... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** *RIT1*
* **Protein Change:** ENSP00000357306.3:p.Glu81Gly
* **ClinVar Variation ID:** VCV000183405 (Accession: 183405)
* **Associated Condition:** Noonan syndrome (OMIM: 615355)
* **Data Timestamp:** 2026-06-28 00:00:00
* **Reference Id... | VCV000183405 | 32 | Definitive | 183,405 | broader_clingen_entity | RIT1 | 14 | Tier 1 — highest priority | 5 | 615355 | RIT1
183405
VCV000183405
ENSP00000357306.3:p.Glu81Gly
14
Tier 1 — highest priority
32.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
332dc0e1a42d | Noonan syndrome | ENSP00000357306.3:p.Glu81Gly | 332dc0e1a42d | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Ser222Pro
ClinVar ID: 4710025
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000302486.5:p.Ser222Pro variant (ClinVar ID: 4710025) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority for the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
### Instructions
1. **Analyze the Data**: Review the variant details, investigation ... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** MAP2K1
* **Protein Variant:** ENSP00000302486.5:p.Ser222Pro
* **ClinVar Accession:** 4710025 (VCV004710025)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615279)
## Computational Evidence
The following comput... | VCV004710025 | 33 | Definitive | 4,710,025 | broader_clingen_entity | MAP2K1 | 13 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
4710025
VCV004710025
ENSP00000302486.5:p.Ser222Pro
13
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d63d6db4bc76 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Ser222Pro | d63d6db4bc76 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Asp245Asn
ClinVar ID: 3253409
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a com... | The ENSP00000302486.5:p.Asp245Asn variant (ClinVar ID: 3253409) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze Computational Prioritization Data for Genetic Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
**Key Requirement:** Clearly explain that "Tier 1" represents a computational priority for further study an... | ### Computational Prioritization Analysis: *MAP2K1* c.734A>C (p.Asp245Asn)
**Variant Identification**
* **Gene:** *MAP2K1*
* **Protein Change:** ENSP00000302486.5:p.Asp245Asn
* **ClinVar Variation ID:** 3253409 (VCV003253409)
* **Associated Condition:** Cardiofaciocutaneous (CFC) Syndrome
#### 1. Computationa... | VCV003253409 | 33 | Definitive | 3,253,409 | broader_clingen_entity | MAP2K1 | 13 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3253409
VCV003253409
ENSP00000302486.5:p.Asp245Asn
13
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
5c12f9f75bd0 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Asp245Asn | 5c12f9f75bd0 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Pro193Leu
ClinVar ID: 3373528
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity conte... | The ENSP00000302486.5:p.Pro193Leu variant (ClinVar ID: 3373528) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Role
Act as an expert clinical geneticist and variant interpreter.
# Task
Analyze the provided computational prioritization data for the specified gene variant candidate. Your analysis must:
1. Integrate the ClinGen and GenCC validity contexts found in the data.
2. Evaluate whether the current evidence is sufficient... | ### Variant Prioritization Analysis: MAP2K1 p.Pro193Leu
**Variant Identification**
* **Gene:** *MAP2K1*
* **Protein Variant:** ENSP00000302486.5:p.Pro193Leu
* **ClinVar Variation ID:** 3373528
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615279)
**Computational Evidence**
The following computation... | VCV003373528 | 33 | Definitive | 3,373,528 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3373528
VCV003373528
ENSP00000302486.5:p.Pro193Leu
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
914b69feca3a | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Pro193Leu | 914b69feca3a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Asn581Thr
ClinVar ID: 376376
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Contextualize the gene–disease relationship acc... | The ENSP00000493543.1:p.Asn581Thr variant (ClinVar ID: 376376) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional ... | Analyze the computational prioritization data provided below for the BRAF gene variant selected as a candidate for additional functional investigation.
### Input Data
```
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Asn581Thr
ClinVar ID: 376376
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Cont... | ### 1. Computational Prioritization Analysis
The variant ENSP00000493543.1:p.Asn581Thr (ClinVar ID: 376376) in the *BRAF* gene has been designated as **Tier 1**, indicating the highest priority for additional functional investigation within this computational framework. This prioritization is driven by the following *... | VCV000376376 | 33 | Definitive | 376,376 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
376376
VCV000376376
ENSP00000493543.1:p.Asn581Thr
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d05a858d5ac0 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Asn581Thr | d05a858d5ac0 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Leu711Pro
ClinVar ID: 3343956
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computat... | The ENSP00000493543.1:p.Leu711Pro variant (ClinVar ID: 3343956) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
**Variant Data:**
```
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Leu711Pro
ClinVar ID: 3343956
Investigatio... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** *BRAF*
* **Protein Variant:** ENSP00000493543.1:p.Leu711Pro
* **ClinVar ID:** 3343956 (VCV003343956)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## Investigation Priority Status
**Priority Tier:** T... | VCV003343956 | 33 | Definitive | 3,343,956 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
3343956
VCV003343956
ENSP00000493543.1:p.Leu711Pro
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
df890350b6a9 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Leu711Pro | df890350b6a9 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: RAF1
Protein variant: ENSP00000251849.4:p.Glu393Ala
ClinVar ID: 283158
Investigation score: 13
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context a... | The ENSP00000251849.4:p.Glu393Ala variant (ClinVar ID: 283158) in RAF1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional ... | # Task: Tier 1 Prioritization Analysis for RAF1 Variant
Based on the computational criteria and raw data provided below, perform the following:
1. **Describe the Tier 1 Prioritization**: Analyze the Variant of Uncertain Significance (VUS) using the provided metrics.
2. **Contextualize Validity**: Incorporate the Clin... | # Tier 1 Prioritization Analysis: RAF1 p.Glu393Ala
**1. Tier 1 Prioritization Description**
The variant ENSP00000251849.4:p.Glu393Ala (ClinVar ID: 283158) is classified as Tier 1, indicating the highest priority for computational investigation. This prioritization is driven by the following explicitly provided computa... | VCV000283158 | 32 | Definitive | 283,158 | exact | RAF1 | 13 | Tier 1 — highest priority | 4 | 611553 | RAF1
283158
VCV000283158
ENSP00000251849.4:p.Glu393Ala
13
Tier 1 — highest priority
32.0
4
Noonan syndrome
Definitive
exact
611553
40496714
10.1016/j.gimo.2025.103430
2026-06-28
34b7604f58f5 | Noonan syndrome | ENSP00000251849.4:p.Glu393Ala | 34b7604f58f5 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Cys532Tyr
ClinVar ID: 40380
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Clarify which additional evidence, including func... | The ENSP00000493543.1:p.Cys532Tyr variant (ClinVar ID: 40380) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following analysis for the specified Variant of Uncertain Significance (VUS):
1. **Describe the Tier 1 Prioritization**: Explain why this variant is classified as "Tier 1 — high... | # Variant Prioritization Analysis: BRAF p.Cys532Tyr
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Cys532Tyr
* **ClinVar Variation ID:** 40380 (VCV000040380)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## 1. Tier 1 Prioritization Rationale
Th... | VCV000040380 | 31 | Definitive | 40,380 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
40380
VCV000040380
ENSP00000493543.1:p.Cys532Tyr
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
5e5265bc4971 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Cys532Tyr | 5e5265bc4971 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Arg238Trp
ClinVar ID: 1757301
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship ... | The ENSP00000262948.4:p.Arg238Trp variant (ClinVar ID: 1757301) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze Genetic Variant Prioritization Data
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
## Instructions
1. **Data Analysis**: Review the variant metrics, including the Investigation score, CADD PHRED score, and co... | # Variant Prioritization Analysis: MAP2K2 p.Arg238Trp
## Variant Identification
* **Gene:** *MAP2K2*
* **Protein Change:** ENSP00000262948.4:p.Arg238Trp
* **ClinVar Accession:** VCV001757301 (ID: 1757301)
* **Associated Condition:** Cardiofaciocutaneous syndrome
* **OMIM Phenotype:** 615280 (Cardiofaciocutaneous syndr... | VCV001757301 | 32 | Definitive | 1,757,301 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
1757301
VCV001757301
ENSP00000262948.4:p.Arg238Trp
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
cb3d140a25be | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Arg238Trp | cb3d140a25be | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Leu525Pro
ClinVar ID: 222077
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context a... | The ENSP00000493543.1:p.Leu525Pro variant (ClinVar ID: 222077) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional ... | Based on the computational criteria and raw data provided below, perform the following tasks regarding the Variant of Uncertain Significance (VUS):
1. **Tier 1 Prioritization Analysis**: Describe the Tier 1 prioritization for this variant using the provided metrics.
2. **Validity Context**: Incorporate the ClinGen (Cl... | ### Variant Prioritization and Interpretation Report
**Variant Identification**
* **Gene:** BRAF
* **Protein Change:** ENSP00000493543.1:p.Leu525Pro
* **ClinVar Identification:** 222077 (VCV000222077)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
#### 1. Tier 1 Prioritization Analys... | VCV000222077 | 32 | Definitive | 222,077 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
222077
VCV000222077
ENSP00000493543.1:p.Leu525Pro
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
a00b956d4172 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Leu525Pro | a00b956d4172 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Lys591Glu
ClinVar ID: 1711064
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a compu... | The ENSP00000493543.1:p.Lys591Glu variant (ClinVar ID: 1711064) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Prioritization Data
Analyze the following computational prioritization data for a gene variant selected as a candidate for additional functional investigation.
## Input Data
```
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Lys591Glu
ClinVar ID: 1711064
Investigation score: 11
CADD PHR... | ### Computational Prioritization Analysis: BRAF c.1772A>G (p.Lys591Glu)
**Variant Identification**
* **Gene:** *BRAF*
* **Protein Change:** ENSP00000493543.1:p.Lys591Glu (K591E)
* **ClinVar Accession:** VCV001711064 (Variation ID: 1711064)
* **Associated Condition:** Cardiofaciocutaneous syndrome (CFC)
#### 1... | VCV001711064 | 31 | Definitive | 1,711,064 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
1711064
VCV001711064
ENSP00000493543.1:p.Lys591Glu
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
ab5a50d9934a | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Lys591Glu | ab5a50d9934a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Asn581His
ClinVar ID: 55794
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including fun... | The ENSP00000493543.1:p.Asn581His variant (ClinVar ID: 55794) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional p... | # Role and Objective
You are an expert genetic variant analyst. Your task is to analyze the provided computational prioritization data for a specific gene variant and determine the additional evidence required for its clinical reclassification.
# Input Data
The following raw data describes the variant candidate:
```
... | # Variant Prioritization and Evidence Gap Analysis: BRAF p.Asn581His
## Computational Evidence Summary
The following computational metrics were explicitly provided for the variant **BRAF** **ENSP00000493543.1:p.Asn581His** (ClinVar ID: 55794; VCV000055794):
* **CADD PHRED Score:** 33.0
* **Investigation Score:** ... | VCV000055794 | 33 | Definitive | 55,794 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
55794
VCV000055794
ENSP00000493543.1:p.Asn581His
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
ed4fd757ad9d | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Asn581His | ed4fd757ad9d | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Val131Met
ClinVar ID: 46234
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including fu... | The ENSP00000262948.4:p.Val131Met variant (ClinVar ID: 46234) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following two tasks:
1. **Describe the Tier 1 Prioritization**: Analyze the provided Variant of Uncertain Significance (VUS) for the gene *MAP2K2*. Explain why this variant meet... | # Variant Prioritization Analysis: MAP2K2 p.Val131Met
## Variant Identification
* **Gene:** *MAP2K2*
* **Protein Variant:** ENSP00000262948.4:p.Val131Met
* **ClinVar ID:** 46234 (VCV000046234)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM #615280; CFC4)
* **Current Classification:** Variant of Uncert... | VCV000046234 | 33 | Definitive | 46,234 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
46234
VCV000046234
ENSP00000262948.4:p.Val131Met
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
0797866c021a | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Val131Met | 0797866c021a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Val669Met
ClinVar ID: 2231382
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computat... | The ENSP00000493543.1:p.Val669Met variant (ClinVar ID: 2231382) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Assess Clinical Investigation Priority for RASopathy Variant
Analyze the provided variant data from the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline. Your goal is to assess the clinical investigation priority and clearly explain the implications of the assigned tier.
## Instructio... | ### Variant Prioritization Assessment: BRAF p.Val669Met
**Variant Identification**
* **Gene:** BRAF
* **Protein Change:** ENSP00000493543.1:p.Val669Met
* **ClinVar Variation ID:** 2231382
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
* **Pipeline Report Date:** 2026-06-28
**Comput... | VCV002231382 | 32 | Definitive | 2,231,382 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
2231382
VCV002231382
ENSP00000493543.1:p.Val669Met
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
abef21737c86 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Val669Met | abef21737c86 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: RAF1
Protein variant: ENSP00000251849.4:p.Arg398His
ClinVar ID: 1034621
Investigation score: 14
CADD PHRED: 35.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and state w... | The ENSP00000251849.4:p.Arg398His variant (ClinVar ID: 1034621) in RAF1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 35.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Clinical Variant Evidence Summary
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity.
## Instructions
1. **Contextualize Validity**: Integrate ClinGen (Clinical Genome Resource) and GenCC (Gene Curation Coalition) validity... | # Clinical Variant Evidence Summary
**Variant Identification**
* **Gene:** RAF1
* **Protein Variant:** p.Arg398His (ENSP00000251849.4)
* **ClinVar ID:** 1034621 (VCV001034621)
* **Associated Condition:** Noonan syndrome (OMIM: 611553)
* **Current Classification Context:** Variant of Uncertain Significance (V... | VCV001034621 | 35 | Definitive | 1,034,621 | exact | RAF1 | 14 | Tier 1 — highest priority | 4 | 611553 | RAF1
1034621
VCV001034621
ENSP00000251849.4:p.Arg398His
14
Tier 1 — highest priority
35.0
4
Noonan syndrome
Definitive
exact
611553
40496714
10.1016/j.gimo.2025.103430
2026-06-28
f808431437dd | Noonan syndrome | ENSP00000251849.4:p.Arg398His | f808431437dd | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Gly132Asp
ClinVar ID: 30170
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context an... | The ENSP00000262948.4:p.Gly132Asp variant (ClinVar ID: 30170) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Instructions
1. **Analyze the Data**: Review the provided variant metrics, includi... | ### Priority Assessment
The variant MAP2K2 ENSP00000262948.4:p.Gly132Asp (ClinVar ID: 30170) is categorized as **Tier 1 — highest priority** for clinical investigation by the unified RASopathy VUS Series pipeline. This prioritization is driven by the following computational metrics:
* **Investigation Score:** 11
* ... | VCV000030170 | 31 | Definitive | 30,170 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
30170
VCV000030170
ENSP00000262948.4:p.Gly132Asp
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
f9866a8aab1e | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Gly132Asp | f9866a8aab1e | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Met546Arg
ClinVar ID: 1354979
Investigation score: 11
CADD PHRED: 30.0
Concordant predictors: 5
Clarify which additional evidence, including ... | The ENSP00000358464.5:p.Met546Arg variant (ClinVar ID: 1354979) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 30.0, and support from 5 concordant computational predictor(s). Additiona... | You are an expert geneticist and variant classifier. Analyze the following computational prioritization data for a candidate variant selected for additional functional investigation regarding Noonan syndrome-like disorder with loose anagen hair.
### Variant Data
The following raw data points describe the variant conte... | ### Computational Evidence Summary
The candidate variant *SHOC2* p.Met546Arg (ENSP00000358464.5; ClinVar ID: 1354979) was assigned Tier 1 (highest investigation priority) based on the following computational metrics:
* **Investigation Score**: 11
* **CADD PHRED**: 30.0
* **Concordant Predictor Count**: 5
**Discl... | VCV001354979 | 30 | Definitive | 1,354,979 | broader_clingen_entity | SHOC2 | 11 | Tier 1 — highest priority | 5 | 607721 | SHOC2
1354979
VCV001354979
ENSP00000358464.5:p.Met546Arg
11
Tier 1 — highest priority
30.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
0f516cb06fd4 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Met546Arg | 0f516cb06fd4 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Lys483Ile
ClinVar ID: 1198003
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a compu... | The ENSP00000493543.1:p.Lys483Ile variant (ClinVar ID: 1198003) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Prioritization Data for BRAF Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
**Critical Requirement:** Clearly explain that "Tier 1" represents a computational priority for further study ... | ### Computational Prioritization Analysis: *BRAF* p.Lys483Ile
**Variant Identification**
* **Gene:** *BRAF*
* **Protein Change:** ENSP00000493543.1:p.Lys483Ile
* **ClinVar Accession:** VCV001198003 (ClinVar ID: 1198003)
* **Associated Condition:** Cardiofaciocutaneous syndrome (CFC)
#### 1. Computational Evid... | VCV001198003 | 33 | Definitive | 1,198,003 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
1198003
VCV001198003
ENSP00000493543.1:p.Lys483Ile
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b29d4e3d8ff5 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Lys483Ile | b29d4e3d8ff5 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Asp594Gly
ClinVar ID: 13972
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Contextualize the gene–disease relationship accor... | The ENSP00000493543.1:p.Asp594Gly variant (ClinVar ID: 13972) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: VUS Tier 1 Prioritization Analysis
Based on the computational criteria and raw data provided below, describe the **Tier 1 prioritization** (highest priority) for the specified Variant of Uncertain Significance (VUS).
## Instructions
1. **Analyze Computational Criteria**: Evaluate the provided metrics, includi... | # Variant Prioritization Analysis: Tier 1
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Asp594Gly
* **ClinVar ID:** 13972 (VCV000013972)
* **Prioritization Tier:** Tier 1 — Highest Priority
## Computational Evidence Assessment
The following computational metrics, report... | VCV000013972 | 31 | Definitive | 13,972 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
13972
VCV000013972
ENSP00000493543.1:p.Asp594Gly
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
5d7cb7985875 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Asp594Gly | 5d7cb7985875 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly596Cys
ClinVar ID: 44814
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including func... | The ENSP00000493543.1:p.Gly596Cys variant (ClinVar ID: 44814) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following two steps:
1. **Describe the Tier 1 Prioritization**: Analyze the Variant of Uncertain Significance (VUS) using the provided metrics (Investigation score, CADD PHRED, ... | # Variant Prioritization Analysis: BRAF p.Gly596Cys
## 1. Tier 1 Prioritization Analysis
The variant **BRAF p.Gly596Cys** (ClinVar ID: 44814) is currently categorized as a Variant of Uncertain Significance (VUS). Based on the provided computational metrics and gene-disease validity data, it qualifies as **Tier 1 — hi... | VCV000044814 | 33 | Definitive | 44,814 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
44814
VCV000044814
ENSP00000493543.1:p.Gly596Cys
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
0cf8a807c441 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly596Cys | 0cf8a807c441 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS2
Protein variant: ENSP00000216373.5:p.Arg630Cys
ClinVar ID: 2904513
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computat... | The ENSP00000216373.5:p.Arg630Cys variant (ClinVar ID: 2904513) in SOS2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 5 concordant computational predictor(s). Additional... | # Task: Assess Clinical Investigation Priority
Analyze the following variant data identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
**Requirements:**
1. **Assess Priority:** Evaluate the clinical investigation priority based on the provided metrics.
2. **Clarify Tier Status... | ### Variant Investigation Priority Assessment
**Variant Identification**
* **Gene:** SOS2
* **Protein Variant:** ENSP00000216373.5:p.Arg630Cys
* **ClinVar ID:** 2904513
**Computational Evidence**
The following computational metrics are reported exactly as provided by the prioritization pipeline. These values re... | VCV002904513 | 33 | Definitive | 2,904,513 | broader_clingen_entity | SOS2 | 11 | Tier 1 — highest priority | 5 | 616559 | SOS2
2904513
VCV002904513
ENSP00000216373.5:p.Arg630Cys
11
Tier 1 — highest priority
33.0
5
Noonan syndrome
Definitive
broader_clingen_entity
616559
40496714
10.1016/j.gimo.2025.103430
2026-06-28
7c5c5a916107 | Noonan syndrome | ENSP00000216373.5:p.Arg630Cys | 7c5c5a916107 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Pro162Leu
ClinVar ID: 4744148
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 5
Contextualize the gene–disease relationship according to ... | The ENSP00000358464.5:p.Pro162Leu variant (ClinVar ID: 4744148) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additiona... | # Task: Genetic Variant Analysis and Summary
Analyze the provided data for a Tier 1 Variant of Uncertain Significance (VUS) and generate a comprehensive summary. Your response must address the following two objectives:
1. **Computational Evidence and Validity**: Summarize the computational evidence level and the gene... | # Variant Analysis Summary: SHOC2 ENSP00000358464.5:p.Pro162Leu
## 1. Variant Identification
* **Gene:** SHOC2
* **Protein Variant:** ENSP00000358464.5:p.Pro162Leu
* **ClinVar ID:** 4744148 (VCV004744148)
* **Current Classification:** Variant of Uncertain Significance (VUS)
* **Prioritization Tier:** Tier 1 (Highest P... | VCV004744148 | 32 | Definitive | 4,744,148 | broader_clingen_entity | SHOC2 | 12 | Tier 1 — highest priority | 5 | 607721 | SHOC2
4744148
VCV004744148
ENSP00000358464.5:p.Pro162Leu
12
Tier 1 — highest priority
32.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
7b743cb27a21 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Pro162Leu | 7b743cb27a21 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.His574Tyr
ClinVar ID: 44810
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clarify which additional evidence, including functional stud... | The ENSP00000493543.1:p.His574Tyr variant (ClinVar ID: 44810) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: Analyze VUS Classification and Evidence Requirements
You are an expert geneticist and variant curator. Based on the provided data for a Tier 1 Variant of Uncertain Significance (VUS), perform the following analysis:
1. **Summarize Current Evidence**: Evaluate the computational evidence level and gene–disease ... | # Variant Prioritization Analysis: BRAF p.His574Tyr
## 1. Computational Evidence Summary
The variant **BRAF** ENSP00000493543.1:p.His574Tyr (ClinVar ID: 44810 / VCV000044810) is currently classified as a Variant of Uncertain Significance (VUS) and designated as **Tier 1 — highest priority** for clinical review and re... | VCV000044810 | 32 | Definitive | 44,810 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
44810
VCV000044810
ENSP00000493543.1:p.His574Tyr
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d05ded4dcea3 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.His574Tyr | d05ded4dcea3 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: PTPN11
Protein variant: ENSP00000340944.3:p.Arg498Trp
ClinVar ID: 40553
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Contextualize the gene–disease relationship acc... | The ENSP00000340944.3:p.Arg498Trp variant (ClinVar ID: 40553) in PTPN11 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization Analysis
Based on the computational criteria and raw data provided below, describe the **Tier 1 prioritization** (highest priority) for the specified Variant of Uncertain Significance (VUS).
## Instructions
1. **Analyze Computational Criteria**: Evaluate the provided metrics, includ... | # Tier 1 Prioritization Analysis: PTPN11 p.Arg498Trp
## Variant Identification
* **Gene:** *PTPN11*
* **Protein Variant:** ENSP00000340944.3:p.Arg498Trp
* **ClinVar Variation ID:** 40553
## Computational Evidence Metrics
The following computational values were extracted from the provided input:
* **Investigation Scor... | VCV000040553 | 33 | Definitive | 40,553 | exact | PTPN11 | 13 | Tier 1 — highest priority | 4 | 176876 | PTPN11
40553
VCV000040553
ENSP00000340944.3:p.Arg498Trp
13
Tier 1 — highest priority
33.0
4
Noonan syndrome with multiple lentigines
Definitive
exact
176876
40496714
10.1016/j.gimo.2025.103430
2026-06-28
fffcdbe262cd | Noonan syndrome with multiple lentigines | ENSP00000340944.3:p.Arg498Trp | fffcdbe262cd | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Gly128Val
ClinVar ID: 13352
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a compu... | The ENSP00000302486.5:p.Gly128Val variant (ClinVar ID: 13352) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Prioritization Data for Genetic Variant
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
**Critical Requirement:** Clearly explain that "Tier 1" represents a computational priority for further stu... | ### 1. Variant Summary
The variant under investigation is located in the **MAP2K1** gene, specified by the protein change **ENSP00000302486.5:p.Gly128Val**. It is cataloged under ClinVar ID **13352** (VCV000013352). Based on the provided data, this variant is associated with **cardiofaciocutaneous syndrome** (OMIM: 615... | VCV000013352 | 32 | Definitive | 13,352 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
13352
VCV000013352
ENSP00000302486.5:p.Gly128Val
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
78493739ae76 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Gly128Val | 78493739ae76 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: PTPN11
Protein variant: ENSP00000340944.3:p.Gly503Glu
ClinVar ID: 40561
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational pri... | The ENSP00000340944.3:p.Gly503Glu variant (ClinVar ID: 40561) in PTPN11 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Evidence and Gene-Disease Validity
You are an expert genetic counselor and bioinformatician. Your task is to summarize the computational evidence level and gene–disease validity for the provided Variant of Uncertain Significance (VUS) data.
## Instructions
1. **Data Analysis**: Review ... | ### Computational Evidence and Gene-Disease Validity Assessment: *PTPN11* c.1507G>A (p.Gly503Glu)
**Variant Identification**
* **Gene:** *PTPN11*
* **Protein Change:** p.Gly503Glu (ENSP00000340944.3)
* **ClinVar Variation ID:** 40561 (VCV000040561)
* **Current Clinical Status:** Variant of Uncertain Significan... | VCV000040561 | 33 | Definitive | 40,561 | exact | PTPN11 | 13 | Tier 1 — highest priority | 4 | 176876 | PTPN11
40561
VCV000040561
ENSP00000340944.3:p.Gly503Glu
13
Tier 1 — highest priority
33.0
4
Noonan syndrome with multiple lentigines
Definitive
exact
176876
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b3492f774fd7 | Noonan syndrome with multiple lentigines | ENSP00000340944.3:p.Gly503Glu | b3492f774fd7 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Gly213Arg
ClinVar ID: 2905812
Investigation score: 12
CADD PHRED: 34.0
Concordant predictors: 4
Clarify which additional evidence, including ... | The ENSP00000302486.5:p.Gly213Arg variant (ClinVar ID: 2905812) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 34.0, and support from 4 concordant computational predictor(s). Addition... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following two tasks:
1. **Describe the Tier 1 Prioritization**: Analyze why this Variant of Uncertain Significance (VUS) is classified as "Tier 1" (highest priority). Specifical... | # Variant Prioritization Analysis: MAP2K1 p.Gly213Arg
## 1. Tier 1 Prioritization Rationale
The variant **MAP2K1 p.Gly213Arg** (ClinVar ID: 2905812) is currently classified as a Variant of Uncertain Significance (VUS) and has been assigned **Tier 1** status, indicating the highest priority for further clinical invest... | VCV002905812 | 34 | Definitive | 2,905,812 | broader_clingen_entity | MAP2K1 | 12 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
2905812
VCV002905812
ENSP00000302486.5:p.Gly213Arg
12
Tier 1 — highest priority
34.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
59284ab31416 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Gly213Arg | 59284ab31416 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Glu501Val
ClinVar ID: 40374
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Contextualize the gene–disease relationship accor... | The ENSP00000493543.1:p.Glu501Val variant (ClinVar ID: 40374) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional p... | Based on the computational criteria and raw data provided below, perform the following tasks:
1. **Tier 1 Prioritization Analysis**: Describe the Tier 1 (highest priority) classification for the specified Variant of Uncertain Significance (VUS) using the provided metrics:
- **Investigation Score**: 11
- **CADD P... | ### Tier 1 Prioritization Analysis
The variant **BRAF ENSP00000493543.1:p.Glu501Val** (ClinVar ID: 40374) has been assigned a **Tier 1** classification, indicating the highest priority for computational investigation. This designation is based on the following aggregated computational metrics provided in the input dat... | VCV000040374 | 33 | Definitive | 40,374 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
40374
VCV000040374
ENSP00000493543.1:p.Glu501Val
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6b71f1dca5ee | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Glu501Val | 6b71f1dca5ee | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Lys534Glu
ClinVar ID: 1696275
Investigation score: 13
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computat... | The ENSP00000384675.2:p.Lys534Glu variant (ClinVar ID: 1696275) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Requirements
1. **Priority Assessment**: Analyze the provided metrics to determine... | # Clinical Investigation Priority Assessment
## Variant Identification and Condition Context
* **Gene:** *SOS1*
* **Protein Variant:** p.Lys534Glu (ENSP00000384675.2)
* **ClinVar Variation ID:** 1696275 (VCV001696275)
* **Associated Condition:** Noonan syndrome (RASopathy spectrum)
This assessment evaluates t... | VCV001696275 | 32 | Definitive | 1,696,275 | exact | SOS1 | 13 | Tier 1 — highest priority | 4 | 163950 | SOS1
1696275
VCV001696275
ENSP00000384675.2:p.Lys534Glu
13
Tier 1 — highest priority
32.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
e53af2c942ac | Noonan syndrome | ENSP00000384675.2:p.Lys534Glu | e53af2c942ac | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: HRAS
Protein variant: p.Val8Gly
ClinVar ID: 4803234
Investigation score: 8
CADD PHRED: 26.6
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational priority and ... | The p.Val8Gly variant (ClinVar ID: 4803234) in HRAS was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 8, a CADD PHRED score of 26.6, and support from 4 concordant computational predictor(s). Additional pipeline evidence: l... | # Task: Describe Tier 1 Prioritization for a Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, describe the Tier 1 prioritization for this specific variant.
**Requirements:**
1. Analyze the provided metrics (Investigation score, CADD PHRED, Concordant predictors... | ### Tier 1 Computational Prioritization Report: *HRAS* c.22G>A (p.Val8Gly)
**Variant Identification**
* **Gene:** *HRAS*
* **Protein Change:** p.Val8Gly
* **ClinVar Variation ID:** 4803234 (VCV004803234)
* **Current Clinical Classification:** Variant of Uncertain Significance (VUS)
* **Associated Condition:*... | VCV004803234 | 26.6 | Definitive | 4,803,234 | exact | HRAS | 8 | Tier 1 — highest priority | 4 | 218040 | HRAS
4803234
VCV004803234
p.Val8Gly
8
Tier 1 — highest priority
26.6
4
Costello syndrome
Definitive
exact
218040
40496714
10.1016/j.gimo.2025.103430
2026-06-28
d08690c52c2e | Costello syndrome | p.Val8Gly | d08690c52c2e | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Trp476Gly
ClinVar ID: 1711045
Investigation score: 11
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including func... | The ENSP00000493543.1:p.Trp476Gly variant (ClinVar ID: 1711045) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Clinical Investigation Priority Assessment
Act as a clinical genetics expert. Analyze the provided variant data from the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline to assess its clinical investigation priority and define the evidence required for reclassification.
## Definitions... | # Clinical Investigation Priority Assessment: BRAF p.Trp476Gly
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Trp476Gly
* **ClinVar ID:** 1711045
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## Computational Evidence Metrics
The following comp... | VCV001711045 | 33 | Definitive | 1,711,045 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
1711045
VCV001711045
ENSP00000493543.1:p.Trp476Gly
11
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
5132352647bb | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Trp476Gly | 5132352647bb | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Ser222Pro
ClinVar ID: 3636797
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity conte... | The ENSP00000262948.4:p.Ser222Pro variant (ClinVar ID: 3636797) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Role
Act as an expert clinical geneticist and variant curator.
# Task
Analyze the provided computational prioritization data for the specified gene variant candidate. Based on this data, perform the following:
1. **Contextualize Validity**: Integrate the provided ClinGen and GenCC validity evidence.
2. **Evaluate Ev... | ### Variant Prioritization and Evidence Analysis
**Variant Identification**
* **Gene:** MAP2K2
* **Protein Variant:** ENSP00000262948.4:p.Ser222Pro
* **ClinVar Accession:** 3636797 (VCV003636797)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615280)
**1. Computational Evidence Report**
The followin... | VCV003636797 | 32 | Definitive | 3,636,797 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
3636797
VCV003636797
ENSP00000262948.4:p.Ser222Pro
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
16f7df9dbfc3 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Ser222Pro | 16f7df9dbfc3 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Ala481Thr
ClinVar ID: 1814974
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship ac... | The ENSP00000493543.1:p.Ala481Thr variant (ClinVar ID: 1814974) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | Analyze the provided computational prioritization data for the candidate variant selected for additional functional investigation.
**Data Input:**
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Ala481Thr
ClinVar ID: 1814974
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Contextual Data:
BRAF
1814... | ### Variant Prioritization Analysis: BRAF ENSP00000493543.1:p.Ala481Thr
**1. Computational Evidence Analysis**
The candidate variant BRAF ENSP00000493543.1:p.Ala481Thr (ClinVar ID: 1814974) has been assigned a **Tier 1 — highest priority** classification for additional functional investigation. This designation is jus... | VCV001814974 | 32 | Definitive | 1,814,974 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
1814974
VCV001814974
ENSP00000493543.1:p.Ala481Thr
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
e7536780dcd5 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Ala481Thr | e7536780dcd5 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Tyr89His
ClinVar ID: 183411
Investigation score: 11
CADD PHRED: 30.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computational prior... | The ENSP00000357306.3:p.Tyr89His variant (ClinVar ID: 183411) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 30.0, and support from 5 concordant computational predictor(s). Additional p... | # Task: Analyze Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) detailed below.
**Important Clarification**: Clearly explain that a "Tier 1" classification represents a **computational priorit... | ### Analysis of Computational Evidence and Gene-Disease Validity for *RIT1* p.Tyr89His (ClinVar ID: 183411)
#### 1. Summary of Computational Evidence
The variant *RIT1* c.266A>C (p.Tyr89His), identified under ClinVar accession VCV000183411, has been assigned a **Tier 1** status, indicating the highest priority for com... | VCV000183411 | 30 | Definitive | 183,411 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 5 | 615355 | RIT1
183411
VCV000183411
ENSP00000357306.3:p.Tyr89His
11
Tier 1 — highest priority
30.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
a1bf991507b6 | Noonan syndrome | ENSP00000357306.3:p.Tyr89His | a1bf991507b6 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Phe133Leu
ClinVar ID: 4848424
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and state... | The ENSP00000262948.4:p.Phe133Leu variant (ClinVar ID: 4848424) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze VUS Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) classified as Tier 1 using the data provided below.
**Requirements:**
1. **Evidence Summary**: Detail the computational evid... | # Variant Prioritization and Evidence Analysis Report
**Gene:** MAP2K2
**Protein Variant:** ENSP00000262948.4:p.Phe133Leu
**ClinVar Accession:** 4848424 (VCV004848424)
**Associated Condition:** Cardiofaciocutaneous Syndrome (CFC)
**OMIM Phenotype:** 615280 (Cardiofaciocutaneous Syndrome 4; CFC4)
---
## 1. Co... | VCV004848424 | 32 | Definitive | 4,848,424 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
4848424
VCV004848424
ENSP00000262948.4:p.Phe133Leu
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
be9bac8ab69f | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Phe133Leu | be9bac8ab69f | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Tyr58Cys
ClinVar ID: 1779149
Investigation score: 12
CADD PHRED: 31.0
Concordant predictors: 5
Clarify which additional evidence, including functional stu... | The ENSP00000357306.3:p.Tyr58Cys variant (ClinVar ID: 1779149) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additional ... | # Task: Genetic Variant Evidence Analysis
Analyze the provided data for the Tier 1 Variant of Uncertain Significance (VUS) below. A VUS is a genetic change with unknown clinical impact, and "Tier 1" indicates the highest priority for review.
## Instructions
1. **Summarize Current Evidence**: Based on the data provide... | # Genetic Variant Evidence Analysis: RIT1 p.Tyr58Cys
**Variant Identification**
* **Gene:** RIT1
* **Protein Change:** ENSP00000357306.3:p.Tyr58Cys
* **ClinVar Accession:** 1779149
* **Current Classification:** Variant of Uncertain Significance (VUS)
* **Prioritization Tier:** Tier 1 (Highest Priority for Review)
* **... | VCV001779149 | 31 | Definitive | 1,779,149 | broader_clingen_entity | RIT1 | 12 | Tier 1 — highest priority | 5 | 615355 | RIT1
1779149
VCV001779149
ENSP00000357306.3:p.Tyr58Cys
12
Tier 1 — highest priority
31.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
304ef5837c0b | Noonan syndrome | ENSP00000357306.3:p.Tyr58Cys | 304ef5837c0b | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Gly135Arg
ClinVar ID: 2190492
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Clarify which additional evidence, including... | The ENSP00000262948.4:p.Gly135Arg variant (ClinVar ID: 2190492) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze Computational Prioritization Data for Gene Variant Reclassification
You are an expert geneticist and variant curator. Your goal is to analyze the provided computational prioritization data for a specific gene variant candidate and determine the additional evidence required for its reclassification.
##... | # Variant Prioritization Analysis: MAP2K2 p.Gly135Arg
## Variant Identification
* **Gene:** MAP2K2
* **Protein Variant:** ENSP00000262948.4:p.Gly135Arg
* **ClinVar Identification:** 2190492 (VCV002190492)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615280)
## Computational Evidence Report
The fol... | VCV002190492 | 33 | Definitive | 2,190,492 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
2190492
VCV002190492
ENSP00000262948.4:p.Gly135Arg
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
9842992c9e0a | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Gly135Arg | 9842992c9e0a | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Pro236Leu
ClinVar ID: 591250
Investigation score: 11
CADD PHRED: 35.0
Concordant predictors: 3
Clarify which additional evidence, including ... | The ENSP00000262948.4:p.Pro236Leu variant (ClinVar ID: 591250) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 35.0, and support from 3 concordant computational predictor(s). Additiona... | # Role
You are an expert clinical geneticist and variant curator specializing in the ACMG/AMP guidelines for variant interpretation.
# Task
Analyze the provided computational prioritization data for a specific gene variant selected as a candidate for additional functional investigation. Based on this data, clarify the... | ### Variant Prioritization Analysis: MAP2K2 p.Pro236Leu
**Variant Summary**
* **Gene:** *MAP2K2*
* **Protein Variant:** ENSP00000262948.4:p.Pro236Leu
* **ClinVar ID:** 591250
* **Gene-Disease Validity:** Definitive (ClinGen GCEP)
* **Condition Match:** Broader ClinGen entity (Cardiofaciocutaneous syndrome; O... | VCV000591250 | 35 | Definitive | 591,250 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 3 | 615280 | MAP2K2
591250
VCV000591250
ENSP00000262948.4:p.Pro236Leu
11
Tier 1 — highest priority
35.0
3
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
bc38d31dc7cc | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Pro236Leu | bc38d31dc7cc | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Asp249Tyr
ClinVar ID: 1997887
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clarify which additional evidence, including fu... | The ENSP00000262948.4:p.Asp249Tyr variant (ClinVar ID: 1997887) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the following genetic variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline. Based on the provided data, clarify which additional evidence—including functional studies, segregation d... | # Clinical Investigation Priority Assessment
## 1. Investigation Priority Confirmation
Based on the unified RASopathy VUS Series pipeline metrics, the variant **MAP2K2 p.Asp249Tyr** (ClinVar ID: 1997887) is assigned **Tier 1 — highest priority** for clinical investigation. This prioritization is driven by the aggregat... | VCV001997887 | 32 | Definitive | 1,997,887 | broader_clingen_entity | MAP2K2 | 11 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
1997887
VCV001997887
ENSP00000262948.4:p.Asp249Tyr
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6ad661492180 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Asp249Tyr | 6ad661492180 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Lys483Glu
ClinVar ID: 1418218
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a comput... | The ENSP00000493543.1:p.Lys483Glu variant (ClinVar ID: 1418218) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Computational Prioritization Analysis for Variant of Uncertain Significance (VUS)
## Objective
Based on the computational criteria and raw data provided below, describe the **Tier 1 prioritization** status of the specified Variant of Uncertain Significance (VUS).
## Key Requirements
1. **Analysis**: Evaluate... | ### Computational Prioritization Analysis: BRAF p.Lys483Glu (ClinVar ID: 1418218)
**Variant Identification**
* **Gene:** *BRAF*
* **Protein Change:** ENSP00000493543.1:p.Lys483Glu
* **ClinVar Accession:** VCV001418218
* **Associated Condition:** Cardiofaciocutaneous syndrome (CFC)
#### 1. Computational Eviden... | VCV001418218 | 32 | Definitive | 1,418,218 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
1418218
VCV001418218
ENSP00000493543.1:p.Lys483Glu
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
171d947ac804 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Lys483Glu | 171d947ac804 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Val471Phe
ClinVar ID: 40367
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4
Contextualize the gene–disease relationship acco... | The ENSP00000493543.1:p.Val471Phe variant (ClinVar ID: 40367) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 4 concordant computational predictor(s). Additional p... | Analyze the computational prioritization data for the following genetic variant, which has been selected as a candidate for additional functional investigation:
### Variant Data
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Val471Phe
ClinVar ID: 40367
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 4... | ### 1. Computational Evidence Analysis
The variant *BRAF* ENSP00000493543.1:p.Val471Phe (ClinVar ID: 40367) is classified as Tier 1 — highest investigation priority — based on the following computational metrics:
* **CADD PHRED:** 31.0. This score indicates that the variant is predicted to be highly deleterious, pl... | VCV000040367 | 31 | Definitive | 40,367 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
40367
VCV000040367
ENSP00000493543.1:p.Val471Phe
11
Tier 1 — highest priority
31.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
538e85bf938d | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Val471Phe | 538e85bf938d | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: PTPN11
Protein variant: ENSP00000340944.3:p.Gly268Cys
ClinVar ID: 40523
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context an... | The ENSP00000340944.3:p.Gly268Cys variant (ClinVar ID: 40523) in PTPN11 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Required Analysis
1. **Priority Evaluation**: Analyze the provided metrics to determine ... | # Clinical Investigation Priority Assessment: PTPN11 p.Gly268Cys
## Variant Identification
* **Gene:** PTPN11
* **Protein Variant:** ENSP00000340944.3:p.Gly268Cys
* **ClinVar Identification:** 40523 (VCV000040523)
* **Associated Condition:** Noonan syndrome with multiple lentigines (OMIM: 176876)
* **Referen... | VCV000040523 | 33 | Definitive | 40,523 | exact | PTPN11 | 13 | Tier 1 — highest priority | 4 | 176876 | PTPN11
40523
VCV000040523
ENSP00000340944.3:p.Gly268Cys
13
Tier 1 — highest priority
33.0
4
Noonan syndrome with multiple lentigines
Definitive
exact
176876
40496714
10.1016/j.gimo.2025.103430
2026-06-28
bca69f417da7 | Noonan syndrome with multiple lentigines | ENSP00000340944.3:p.Gly268Cys | bca69f417da7 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Leu490Pro
ClinVar ID: 4528113
Investigation score: 13
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship ac... | The ENSP00000384675.2:p.Leu490Pro variant (ClinVar ID: 4528113) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Genetic Variant Prioritization Data
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
## Instructions
1. **Data Analysis**: Review the variant metrics including the investigation score, CADD PHRED score, and con... | # Variant Prioritization Analysis: SOS1 p.Leu490Pro
## Variant Identification
* **Gene:** SOS1 (HGNC:11187)
* **Protein Change:** ENSP00000384675.2:p.Leu490Pro
* **ClinVar ID:** 4528113 (VCV004528113)
* **Associated Condition:** Noonan syndrome
* **Prioritization Tier:** Tier 1 (Highest Priority)
## Computa... | VCV004528113 | 32 | Definitive | 4,528,113 | exact | SOS1 | 13 | Tier 1 — highest priority | 4 | 163950 | SOS1
4528113
VCV004528113
ENSP00000384675.2:p.Leu490Pro
13
Tier 1 — highest priority
32.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
86718fafa9ce | Noonan syndrome | ENSP00000384675.2:p.Leu490Pro | 86718fafa9ce | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Trp531Arg
ClinVar ID: 2430770
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clarify which additional evidence, including functional st... | The ENSP00000493543.1:p.Trp531Arg variant (ClinVar ID: 2430770) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Genetic Variant Analysis and Reclassification Requirements
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize its current computational evidence level and gene–disease validity. Then, identify the specific additional evidence required for reclassification.
## Definitions
- **VUS**:... | # Variant Analysis and Reclassification Requirements
## Computational Evidence Summary
The variant BRAF ENSP00000493543.1:p.Trp531Arg (ClinVar ID: 2430770) exhibits the following computational metrics:
* **CADD PHRED:** 32.0
* **Investigation Score:** 11
* **Concordant Predictor Count:** 4
Based on the investig... | VCV002430770 | 32 | Definitive | 2,430,770 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
2430770
VCV002430770
ENSP00000493543.1:p.Trp531Arg
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
351038c10d23 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Trp531Arg | 351038c10d23 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Leu597Pro
ClinVar ID: 1050479
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clarify which additional evidence, including fu... | The ENSP00000493543.1:p.Leu597Pro variant (ClinVar ID: 1050479) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following:
1. **Describe the Tier 1 Prioritization**: Explain why this Variant of Uncertain Significance (VUS) is classified as "Tier 1" (highest priority) using the provided me... | # Variant Prioritization and Reclassification Analysis: BRAF p.Leu597Pro
**Variant Identification**
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Leu597Pro
* **ClinVar ID:** 1050479
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
* **Current Classification Status:** Variant of Un... | VCV001050479 | 32 | Definitive | 1,050,479 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
1050479
VCV001050479
ENSP00000493543.1:p.Leu597Pro
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
c73c793f78b2 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Leu597Pro | c73c793f78b2 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Ile186Phe
ClinVar ID: 4537787
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Contextualize the gene–disease relationship ... | The ENSP00000302486.5:p.Ile186Phe variant (ClinVar ID: 4537787) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | Analyze the computational prioritization data for the following variant selected as a candidate for additional functional investigation:
### Variant Data
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Ile186Phe
ClinVar ID: 4537787
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
### Contextual Inf... | ### Variant Prioritization Analysis: MAP2K1 p.Ile186Phe
**Variant Identification**
* **Gene:** MAP2K1
* **Protein Variant:** ENSP00000302486.5:p.Ile186Phe
* **ClinVar ID:** 4537787
* **Associated Condition:** Cardiofaciocutaneous syndrome (MIM:615279)
#### 1. Evaluation of Computational Prioritization
The var... | VCV004537787 | 32 | Definitive | 4,537,787 | broader_clingen_entity | MAP2K1 | 12 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
4537787
VCV004537787
ENSP00000302486.5:p.Ile186Phe
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
1efb0322e0c9 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Ile186Phe | 1efb0322e0c9 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Gly143Arg
ClinVar ID: 3659787
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computa... | The ENSP00000358464.5:p.Gly143Arg variant (ClinVar ID: 3659787) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 5 concordant computational predictor(s). Additiona... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the genetic variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
### Instructions
1. **Analyze the Data**: Review the variant details, scores, and as... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** SHOC2
* **Protein Variant:** ENSP00000358464.5:p.Gly143Arg
* **ClinVar ID:** 3659787 (VCV003659787)
* **Associated Condition:** Noonan syndrome-like disorder with loose anagen hair (OMIM: 607721)
## Computational Evidence Summary
The f... | VCV003659787 | 33 | Definitive | 3,659,787 | broader_clingen_entity | SHOC2 | 12 | Tier 1 — highest priority | 5 | 607721 | SHOC2
3659787
VCV003659787
ENSP00000358464.5:p.Gly143Arg
12
Tier 1 — highest priority
33.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
aa90ddcc6945 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Gly143Arg | aa90ddcc6945 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS2
Protein variant: ENSP00000216373.5:p.Cys280Arg
ClinVar ID: 1476142
Investigation score: 11
CADD PHRED: 26.6
Concordant predictors: 5
Contextualize the gene–disease relationship accor... | The ENSP00000216373.5:p.Cys280Arg variant (ClinVar ID: 1476142) in SOS2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 26.6, and support from 5 concordant computational predictor(s). Additional... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Instructions
1. **Analyze Variant Data**: Review the provided gene, protein varian... | ### Clinical Investigation Priority Assessment
**Variant Identification**
* **Gene:** *SOS2*
* **Protein Variant:** ENSP00000216373.5:p.Cys280Arg
* **ClinVar Accession:** 1476142 (VCV001476142)
* **Associated Condition:** Noonan syndrome (OMIM: 616559)
**Clinical Investigation Priority**
The variant is classi... | VCV001476142 | 26.6 | Definitive | 1,476,142 | broader_clingen_entity | SOS2 | 11 | Tier 1 — highest priority | 5 | 616559 | SOS2
1476142
VCV001476142
ENSP00000216373.5:p.Cys280Arg
11
Tier 1 — highest priority
26.6
5
Noonan syndrome
Definitive
broader_clingen_entity
616559
40496714
10.1016/j.gimo.2025.103430
2026-06-28
3a6fe1ce0181 | Noonan syndrome | ENSP00000216373.5:p.Cys280Arg | 3a6fe1ce0181 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Phe82Leu
ClinVar ID: 183407
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 5
Include the ClinGen and GenCC validity context and ... | The ENSP00000357306.3:p.Phe82Leu variant (ClinVar ID: 183407) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additional p... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority for the RASopathy variant of uncertain significance (VUS) identified by the unified pipeline. Use the provided data to evaluate the variant, incorporate ClinGen and GenCC validity contexts, and determine if current evidence s... | # Clinical Investigation Priority Assessment
**Variant Identification**
* **Gene**: *RIT1*
* **Protein Variant**: ENSP00000357306.3:p.Phe82Leu
* **ClinVar ID**: 183407
---
## 1. Priority Assessment
Based on the unified pipeline metrics provided, this variant is assigned **Tier 1 — highest priority** for clinical inv... | VCV000183407 | 31 | Definitive | 183,407 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 5 | 615355 | RIT1
183407
VCV000183407
ENSP00000357306.3:p.Phe82Leu
11
Tier 1 — highest priority
31.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b6a691ac0b24 | Noonan syndrome | ENSP00000357306.3:p.Phe82Leu | b6a691ac0b24 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Asn248Thr
ClinVar ID: 1204943
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 5
Include the ClinGen and GenCC validity context a... | The ENSP00000358464.5:p.Asn248Thr variant (ClinVar ID: 1204943) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additiona... | Assess the clinical investigation priority for the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
### Input Data
The following data points describe the variant and its context:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Asn248Thr
ClinVar ID: 12049... | ### Variant Investigation Priority Assessment
**Variant:** SHOC2 p.Asn248Thr (ENSP00000358464.5)
**ClinVar ID:** 1204943
**Condition:** Noonan syndrome-like disorder with loose anagen hair
#### 1. Gene-Disease Validity Context
The gene-disease relationship for *SHOC2* and Noonan syndrome-like disorder with loose anag... | VCV001204943 | 31 | Definitive | 1,204,943 | broader_clingen_entity | SHOC2 | 11 | Tier 1 — highest priority | 5 | 607721 | SHOC2
1204943
VCV001204943
ENSP00000358464.5:p.Asn248Thr
11
Tier 1 — highest priority
31.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
1c86a0d2bd4d | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Asn248Thr | 1c86a0d2bd4d | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Gly143Glu
ClinVar ID: 1053860
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 5
Include the ClinGen and GenCC validity context a... | The ENSP00000358464.5:p.Gly143Glu variant (ClinVar ID: 1053860) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additiona... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority for the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
## Task Requirements
1. **Priority Assessment**: Evaluate the variant based on the provided metrics.
2. **Cont... | ### Clinical Investigation Priority Assessment
**Variant Identification**
* **Gene:** SHOC2
* **Protein Variant:** ENSP00000358464.5:p.Gly143Glu
* **ClinVar ID:** 1053860 (VCV001053860)
**Computational Evidence**
The unified RASopathy VUS Series pipeline outputs the following values:
* **Investigation Score:*... | VCV001053860 | 32 | Definitive | 1,053,860 | broader_clingen_entity | SHOC2 | 11 | Tier 1 — highest priority | 5 | 607721 | SHOC2
1053860
VCV001053860
ENSP00000358464.5:p.Gly143Glu
11
Tier 1 — highest priority
32.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
7a761d40e1d3 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Gly143Glu | 7a761d40e1d3 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Pro236Ser
ClinVar ID: 4051191
Investigation score: 12
CADD PHRED: 34.0
Concordant predictors: 4
Include the ClinGen and GenCC validity contex... | The ENSP00000262948.4:p.Pro236Ser variant (ClinVar ID: 4051191) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 34.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Tier 1 Prioritization Analysis for Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, generate a detailed description of the Tier 1 prioritization for the specified variant.
## Instructions
1. **Analyze Computational Data**: Evaluate the provided Investig... | # Tier 1 Prioritization Analysis: MAP2K2 p.Pro236Ser
## Variant Identification
* **Gene:** MAP2K2
* **Protein Variant:** ENSP00000262948.4:p.Pro236Ser
* **ClinVar Variation ID:** 4051191 (VCV004051191)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 615280)
## Computational Evidence Analysis
The vari... | VCV004051191 | 34 | Definitive | 4,051,191 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
4051191
VCV004051191
ENSP00000262948.4:p.Pro236Ser
12
Tier 1 — highest priority
34.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
b0010ae54b20 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Pro236Ser | b0010ae54b20 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: RAF1
Protein variant: ENSP00000251849.4:p.Ala373Val
ClinVar ID: 4531874
Investigation score: 13
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000251849.4:p.Ala373Val variant (ClinVar ID: 4531874) in RAF1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization and Reclassification Analysis
Based on the computational criteria and raw data provided below, perform the following analysis for the Variant of Uncertain Significance (VUS):
1. **Describe the Tier 1 Prioritization**: Explain why this variant is classified as "Tier 1 — highest priori... | # Variant Prioritization and Analysis Report
**Variant Identification**
* **Gene:** RAF1
* **Protein Variant:** ENSP00000251849.4:p.Ala373Val
* **ClinVar ID:** 4531874
* **Current Classification:** Variant of Uncertain Significance (VUS)
## 1. Tier 1 Prioritization Rationale
This variant is designated as **Tier 1 — ... | VCV004531874 | 33 | Definitive | 4,531,874 | exact | RAF1 | 13 | Tier 1 — highest priority | 4 | 611553 | RAF1
4531874
VCV004531874
ENSP00000251849.4:p.Ala373Val
13
Tier 1 — highest priority
33.0
4
Noonan syndrome
Definitive
exact
611553
40496714
10.1016/j.gimo.2025.103430
2026-06-28
57c35f06be3e | Noonan syndrome | ENSP00000251849.4:p.Ala373Val | 57c35f06be3e | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Pro676Ser
ClinVar ID: 453148
Investigation score: 11
CADD PHRED: 30.0
Concordant predictors: 4
Clarify which additional evidence, including fu... | The ENSP00000493543.1:p.Pro676Ser variant (ClinVar ID: 453148) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 30.0, and support from 4 concordant computational predictor(s). Additional ... | # Role
You are an expert clinical geneticist and variant curator specializing in ACMG/AMP guideline interpretation.
# Task
Analyze the provided computational prioritization data for a specific gene variant selected as a candidate for additional functional investigation. Based on this data, clarify the specific additio... | # Variant Prioritization Analysis: BRAF p.Pro676Ser
## Variant Identification
* **Gene:** BRAF
* **Protein Variant:** ENSP00000493543.1:p.Pro676Ser
* **ClinVar Variation ID:** 453148
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
## Computational Evidence Summary
The following computational ... | VCV000453148 | 30 | Definitive | 453,148 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
453148
VCV000453148
ENSP00000493543.1:p.Pro676Ser
11
Tier 1 — highest priority
30.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6de74b360bd7 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Pro676Ser | 6de74b360bd7 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K2
Protein variant: ENSP00000262948.4:p.Gly214Arg
ClinVar ID: 981555
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computa... | The ENSP00000262948.4:p.Gly214Arg variant (ClinVar ID: 981555) in MAP2K2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additiona... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
**Requirements:**
1. Analyze the provided variant data to determine its priority leve... | # Clinical Investigation Priority Assessment: MAP2K2 p.Gly214Arg
## Variant Identification
* **Gene:** *MAP2K2* (MEK2; HGNC:6842)
* **Protein Variant:** ENSP00000262948.4:p.Gly214Arg
* **ClinVar Accession:** 981555 (VCV000981555)
* **Associated Condition:** Cardiofaciocutaneous syndrome (MIM 615280)
## Computational ... | VCV000981555 | 32 | Definitive | 981,555 | broader_clingen_entity | MAP2K2 | 12 | Tier 1 — highest priority | 4 | 615280 | MAP2K2
981555
VCV000981555
ENSP00000262948.4:p.Gly214Arg
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615280
40496714
10.1016/j.gimo.2025.103430
2026-06-28
6a1eb4dc21d1 | cardiofaciocutaneous syndrome | ENSP00000262948.4:p.Gly214Arg | 6a1eb4dc21d1 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: HRAS
Protein variant: p.Gly13Cys
ClinVar ID: 12606
Investigation score: 8
CADD PHRED: 23.5
Concordant predictors: 2
Clearly explain that Tier 1 represents a computational priority and not... | The p.Gly13Cys variant (ClinVar ID: 12606) in HRAS was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 8, a CADD PHRED score of 23.5, and support from 2 concordant computational predictor(s). Additional pipeline evidence: lo... | # Task: Assess Clinical Investigation Priority
Analyze the following variant data identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline. Based on the provided metrics, determine the investigation priority and provide a clear explanation.
## Required Output Components
1. **Priorit... | # Variant Investigation Priority Assessment: HRAS p.Gly13Cys
## 1. Priority Assessment
Based on the computational metrics provided by the unified RASopathy VUS Series pipeline, the variant **HRAS p.Gly13Cys** (ClinVar ID: 12606) is assigned **Tier 1 — highest priority** for clinical investigation. This prioritization ... | VCV000012606 | 23.5 | Definitive | 12,606 | exact | HRAS | 8 | Tier 1 — highest priority | 2 | 218040 | HRAS
12606
VCV000012606
p.Gly13Cys
8
Tier 1 — highest priority
23.5
2
Costello syndrome
Definitive
exact
218040
40496714
10.1016/j.gimo.2025.103430
2026-06-28
64e8e8f356d4 | Costello syndrome | p.Gly13Cys | 64e8e8f356d4 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Leu176Ser
ClinVar ID: 1467895
Investigation score: 13
CADD PHRED: 32.0
Concordant predictors: 5
Include the ClinGen and GenCC validity context and state ... | The ENSP00000358464.5:p.Leu176Ser variant (ClinVar ID: 1467895) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additiona... | # Task: Clinical Variant Evidence Summary
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity. Specifically, address the following:
1. **Computational Evidence**: Evaluate the provided metrics (Investigation score, CADD PHRED, Conco... | # Clinical Variant Evidence Summary
**Variant Identification**
* **Gene:** SHOC2
* **Protein Change:** p.Leu176Ser (ENSP00000358464.5)
* **ClinVar Accession:** 1467895 (VCV001467895)
* **Associated Condition:** Noonan syndrome-like disorder with loose anagen hair (OMIM: 607721)
* **Current Classification:** Variant of... | VCV001467895 | 32 | Definitive | 1,467,895 | broader_clingen_entity | SHOC2 | 13 | Tier 1 — highest priority | 5 | 607721 | SHOC2
1467895
VCV001467895
ENSP00000358464.5:p.Leu176Ser
13
Tier 1 — highest priority
32.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
8af652f06281 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Leu176Ser | 8af652f06281 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Gln269Arg
ClinVar ID: 218698
Investigation score: 12
CADD PHRED: 28.9
Concordant predictors: 5
Contextualize the gene–disease relationship acc... | The ENSP00000358464.5:p.Gln269Arg variant (ClinVar ID: 218698) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 28.9, and support from 5 concordant computational predictor(s). Additional... | # Task: VUS Tier 1 Prioritization and Gene-Disease Contextualization
Based on the computational criteria and raw data provided below, perform the following analysis for the specified Variant of Uncertain Significance (VUS):
1. **Tier 1 Prioritization Description**: Describe the rationale for classifying this variant ... | # Variant Prioritization Report: SHOC2 p.Gln269Arg
## Variant Identification
* **Gene:** *SHOC2*
* **Protein Variant:** ENSP00000358464.5:p.Gln269Arg
* **ClinVar Accession:** 218698 (VCV000218698)
* **Associated Condition:** Noonan syndrome-like disorder with loose anagen hair
* **Current Classification:** Variant of ... | VCV000218698 | 28.9 | Definitive | 218,698 | broader_clingen_entity | SHOC2 | 12 | Tier 1 — highest priority | 5 | 607721 | SHOC2
218698
VCV000218698
ENSP00000358464.5:p.Gln269Arg
12
Tier 1 — highest priority
28.9
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
a998c02890a0 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Gln269Arg | a998c02890a0 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly464Glu
ClinVar ID: 13964
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and state whe... | The ENSP00000493543.1:p.Gly464Glu variant (ClinVar ID: 13964) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional p... | # Task: Clinical Variant Evidence Summary
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity. Specifically:
1. **Computational Evidence**: Evaluate the provided metrics (Investigation score, CADD PHRED, Concordant predictors) for t... | # Clinical Variant Evidence Summary
### Variant Identification
* **Gene:** *BRAF*
* **Protein Variant:** p.Gly464Glu (ENSP00000493543.1)
* **ClinVar Identification:** ID 13964 (VCV000013964)
* **Associated Condition:** Cardiofaciocutaneous syndrome (OMIM: 115150)
### Computational Evidence Level
The computati... | VCV000013964 | 32 | Definitive | 13,964 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
13964
VCV000013964
ENSP00000493543.1:p.Gly464Glu
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
ec488e1a26dc | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly464Glu | ec488e1a26dc | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Arg181Met
ClinVar ID: 3721182
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a com... | The ENSP00000302486.5:p.Arg181Met variant (ClinVar ID: 3721182) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Analyze Computational Prioritization Data for Genetic Variant
## Objective
Analyze the provided computational prioritization data for the selected candidate variant intended for additional functional investigation.
## Critical Constraint
You must clearly explain that **Tier 1** represents a **computational p... | ### Variant Summary
The candidate variant under review is located in the **MAP2K1** gene, corresponding to the protein change **ENSP00000302486.5:p.Arg181Met** (ClinVar ID: 3721182; VCV003721182). This variant is associated with the clinical phenotype of **cardiofaciocutaneous syndrome**. The gene-disease relationship ... | VCV003721182 | 32 | Definitive | 3,721,182 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3721182
VCV003721182
ENSP00000302486.5:p.Arg181Met
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
3b9ba2b6401d | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Arg181Met | 3b9ba2b6401d | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Arg452Pro
ClinVar ID: 2442609
Investigation score: 14
CADD PHRED: 33.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a comput... | The ENSP00000384675.2:p.Arg452Pro variant (ClinVar ID: 2442609) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 14, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze VUS Prioritization
Based on the computational criteria provided in the **Input Data** section below, describe the Tier 1 prioritization of this Variant of Uncertain Significance (VUS).
**Requirements:**
1. **Analysis**: Evaluate the variant using the provided metrics (Investigation score, CADD PHRED,... | ### Computational Prioritization Analysis: SOS1 c.1354C>T (p.Arg452Pro)
**Variant Identification**
The variant under evaluation is *SOS1* ENSP00000384675.2:p.Arg452Pro (ClinVar ID: 2442609). This missense substitution occurs within the *SOS1* gene, which is definitively associated with Noonan syndrome (OMIM #163950) a... | VCV002442609 | 33 | Definitive | 2,442,609 | exact | SOS1 | 14 | Tier 1 — highest priority | 4 | 163950 | SOS1
2442609
VCV002442609
ENSP00000384675.2:p.Arg452Pro
14
Tier 1 — highest priority
33.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
02af8eaa8ea4 | Noonan syndrome | ENSP00000384675.2:p.Arg452Pro | 02af8eaa8ea4 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Arg349Thr
ClinVar ID: 3292969
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000302486.5:p.Arg349Thr variant (ClinVar ID: 3292969) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Clinical Investigation Priority Assessment
## Task
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Requirements
1. **Priority Analysis**: Evaluate the variant based on the provide... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** MAP2K1
* **Protein Variant:** ENSP00000302486.5:p.Arg349Thr
* **ClinVar ID:** 3292969
* **Associated Condition:** Cardiofaciocutaneous syndrome
## 1. Priority Analysis
The variant was processed through the unified RASopathy VUS Series ... | VCV003292969 | 32 | Definitive | 3,292,969 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3292969
VCV003292969
ENSP00000302486.5:p.Arg349Thr
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
921ffe16ad64 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Arg349Thr | 921ffe16ad64 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Phe82Val
ClinVar ID: 183408
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computatio... | The ENSP00000357306.3:p.Phe82Val variant (ClinVar ID: 183408) in RIT1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additional p... | Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
**Variant Data:**
```
Gene: RIT1
Protein variant: ENSP00000357306.3:p.Phe82Val
ClinVar ID: 183408
Investigation score: 11
CADD PHRED: 31.0
Concordant predicto... | ### Clinical Investigation Priority Assessment: RIT1 c.244T>G (p.Phe82Val)
**Variant Identification**
* **Gene:** *RIT1*
* **Protein Change:** p.Phe82Val (ENSP00000357306.3)
* **ClinVar Variation ID:** 183408 (VCV000183408)
* **Associated Condition:** Noonan syndrome (OMIM #615355)
#### 1. Computational Evide... | VCV000183408 | 31 | Definitive | 183,408 | broader_clingen_entity | RIT1 | 11 | Tier 1 — highest priority | 5 | 615355 | RIT1
183408
VCV000183408
ENSP00000357306.3:p.Phe82Val
11
Tier 1 — highest priority
31.0
5
Noonan syndrome
Definitive
broader_clingen_entity
615355
40496714
10.1016/j.gimo.2025.103430
2026-06-28
c4acc99f45c1 | Noonan syndrome | ENSP00000357306.3:p.Phe82Val | c4acc99f45c1 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Met620Val
ClinVar ID: 1691521
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computational pri... | The ENSP00000493543.1:p.Met620Val variant (ClinVar ID: 1691521) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) detailed below.
**Important Clarification**: Explicitly state that "Tier 1" represents a **computational priority** for further ... | ### Variant Identification
* **Gene:** *BRAF*
* **Protein Variant:** ENSP00000493543.1:p.Met620Val
* **ClinVar ID:** 1691521 (VCV001691521)
### Computational Evidence Summary
The computational evidence profile for the *BRAF* p.Met620Val variant indicates a high level of predicted deleteriousness based on the pro... | VCV001691521 | 32 | Definitive | 1,691,521 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
1691521
VCV001691521
ENSP00000493543.1:p.Met620Val
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
9989460475eb | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Met620Val | 9989460475eb | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Gly596Arg
ClinVar ID: 3764854
Investigation score: 12
CADD PHRED: 32.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context and state w... | The ENSP00000493543.1:p.Gly596Arg variant (ClinVar ID: 3764854) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Evaluate Gene-Disease Validity and Reclassification Potential
Analyze the provided Variant of Uncertain Significance (VUS) data to summarize the computational evidence level and gene–disease validity. Specifically, incorporate context from ClinGen (Clinical Genome Resource) and GenCC (Gene Curation Coalition) ... | ### Computational Evidence Summary
The variant BRAF ENSP00000493543.1:p.Gly596Arg (ClinVar ID: 3764854) has been assigned a Tier 1 classification, indicating the highest priority for computational investigation, based on the following in silico metrics:
* **CADD PHRED Score:** 32.0
* **Investigation Score:** 12
* ... | VCV003764854 | 32 | Definitive | 3,764,854 | broader_clingen_entity | BRAF | 12 | Tier 1 — highest priority | 4 | 115150 | BRAF
3764854
VCV003764854
ENSP00000493543.1:p.Gly596Arg
12
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
ee74a47228d1 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Gly596Arg | ee74a47228d1 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Based on the computational criteria below, describe the Tier 1 prioritization of this variant of uncertain significance (VUS):
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Gly128Asp
ClinVar ID: 3609725
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a comp... | The ENSP00000302486.5:p.Gly128Asp variant (ClinVar ID: 3609725) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Computational Prioritization Analysis for Variant of Uncertain Significance (VUS)
Based on the computational criteria and raw data provided below, describe the **Tier 1 prioritization** for the specified variant.
### Instructions
1. **Analyze the Data**: Review the provided investigation score, CADD PHRED sco... | ### Computational Prioritization Analysis: MAP2K1 p.Gly128Asp (ClinVar ID: 3609725)
**Variant Identification**
The subject of this analysis is the missense variant **p.Gly128Asp** (ENSP00000302486.5) within the **_MAP2K1_** gene, associated with ClinVar Variation ID **3609725**. This variant is currently classified as... | VCV003609725 | 32 | Definitive | 3,609,725 | broader_clingen_entity | MAP2K1 | 11 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
3609725
VCV003609725
ENSP00000302486.5:p.Gly128Asp
11
Tier 1 — highest priority
32.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
dbe1b3f31b1f | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Gly128Asp | dbe1b3f31b1f | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Asn527Ile
ClinVar ID: 2978506
Investigation score: 11
CADD PHRED: 32.0
Concordant predictors: 5
Contextualize the gene–disease relationship a... | The ENSP00000358464.5:p.Asn527Ile variant (ClinVar ID: 2978506) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 32.0, and support from 5 concordant computational predictor(s). Additiona... | # Task: Analyze Computational Prioritization Data for SHOC2 Variant
You are an expert geneticist and bioinformatician. Analyze the provided computational prioritization data for a candidate variant selected for additional functional investigation.
## Instructions
1. **Data Analysis**: Review the variant metrics prov... | ### Computational Prioritization Analysis: SHOC2 p.Asn527Ile
**Variant Identification**
* **Gene:** SHOC2
* **Protein Variant:** ENSP00000358464.5:p.Asn527Ile
* **ClinVar ID:** 2978506
* **Associated Condition:** Noonan syndrome-like disorder with loose anagen hair
**Computational Evidence Metrics**
The variant was a... | VCV002978506 | 32 | Definitive | 2,978,506 | broader_clingen_entity | SHOC2 | 11 | Tier 1 — highest priority | 5 | 607721 | SHOC2
2978506
VCV002978506
ENSP00000358464.5:p.Asn527Ile
11
Tier 1 — highest priority
32.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
3f0c1dca7000 | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Asn527Ile | 3f0c1dca7000 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: MAP2K1
Protein variant: ENSP00000302486.5:p.Val127Met
ClinVar ID: 1424722
Investigation score: 12
CADD PHRED: 33.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context ... | The ENSP00000302486.5:p.Val127Met variant (ClinVar ID: 1424722) in MAP2K1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 12, a CADD PHRED score of 33.0, and support from 4 concordant computational predictor(s). Addition... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority for the specific genetic variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
## Input Data
The following raw data describes the variant and its context:
```
Gene: MAP2K1
Pro... | ### Clinical Investigation Priority Assessment: MAP2K1 p.Val127Met
**Variant Identification**
* **Gene:** *MAP2K1*
* **Protein Variant:** ENSP00000302486.5:p.Val127Met
* **ClinVar ID:** 1424722
---
#### 1. Priority Analysis
The unified RASopathy VUS Series pipeline has assigned this variant a **Tier 1 — highes... | VCV001424722 | 33 | Definitive | 1,424,722 | broader_clingen_entity | MAP2K1 | 12 | Tier 1 — highest priority | 4 | 615279 | MAP2K1
1424722
VCV001424722
ENSP00000302486.5:p.Val127Met
12
Tier 1 — highest priority
33.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
615279
40496714
10.1016/j.gimo.2025.103430
2026-06-28
27cbdb56d4d3 | cardiofaciocutaneous syndrome | ENSP00000302486.5:p.Val127Met | 27cbdb56d4d3 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Trp537Cys
ClinVar ID: 2872898
Investigation score: 13
CADD PHRED: 34.0
Concordant predictors: 4
Include the ClinGen and GenCC validity context an... | The ENSP00000384675.2:p.Trp537Cys variant (ClinVar ID: 2872898) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 34.0, and support from 4 concordant computational predictor(s). Additional... | # Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the following genetic variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline.
## Variant Data
The following data block contains the variant details, scores, and contextual evidence.... | # Clinical Investigation Priority Assessment
## 1. Priority Assessment
The variant SOS1 p.Trp537Cys (ENSP00000384675.2; ClinVar ID: 2872898) is designated as **Tier 1**, indicating the highest priority for clinical investigation within the unified RASopathy VUS Series pipeline. This prioritization is driven by an **in... | VCV002872898 | 34 | Definitive | 2,872,898 | exact | SOS1 | 13 | Tier 1 — highest priority | 4 | 163950 | SOS1
2872898
VCV002872898
ENSP00000384675.2:p.Trp537Cys
13
Tier 1 — highest priority
34.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
c8c836483e7c | Noonan syndrome | ENSP00000384675.2:p.Trp537Cys | c8c836483e7c | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Analyze the computational prioritization data for this variant selected as a candidate for additional functional investigation:
Gene: BRAF
Protein variant: ENSP00000493543.1:p.Arg575Gly
ClinVar ID: 3027033
Investigation score: 11
CADD PHRED: 34.0
Concordant predictors: 4
Clarify which additional evidence, including f... | The ENSP00000493543.1:p.Arg575Gly variant (ClinVar ID: 3027033) in BRAF was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 34.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Analyze Computational Prioritization Data for BRAF Variant Reclassification
You are an expert geneticist and variant curator. Your goal is to analyze the provided computational prioritization data for a specific gene variant and determine the additional evidence required to support its reclassification.
## In... | # Variant Prioritization Analysis: BRAF p.Arg575Gly (ClinVar ID 3027033)
## 1. Data Interpretation
The candidate variant *BRAF* ENSP00000493543.1:p.Arg575Gly (ClinVar ID 3027033) has been designated **Tier 1 — highest priority** for functional investigation. The computational metrics provided in the input are as foll... | VCV003027033 | 34 | Definitive | 3,027,033 | broader_clingen_entity | BRAF | 11 | Tier 1 — highest priority | 4 | 115150 | BRAF
3027033
VCV003027033
ENSP00000493543.1:p.Arg575Gly
11
Tier 1 — highest priority
34.0
4
cardiofaciocutaneous syndrome
Definitive
broader_clingen_entity
115150
40496714
10.1016/j.gimo.2025.103430
2026-06-28
1c3dd5b3d898 | cardiofaciocutaneous syndrome | ENSP00000493543.1:p.Arg575Gly | 1c3dd5b3d898 | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Summarize the computational evidence level and gene–disease validity associated with this VUS classified as Tier 1:
Gene: SHOC2
Protein variant: ENSP00000358464.5:p.Gly349Asp
ClinVar ID: 933363
Investigation score: 11
CADD PHRED: 31.0
Concordant predictors: 5
Clearly explain that Tier 1 represents a computational pri... | The ENSP00000358464.5:p.Gly349Asp variant (ClinVar ID: 933363) in SHOC2 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 11, a CADD PHRED score of 31.0, and support from 5 concordant computational predictor(s). Additional... | # Task: Analyze Computational Evidence and Gene-Disease Validity
Please summarize the computational evidence level and gene–disease validity for the Variant of Uncertain Significance (VUS) detailed below.
**Key Definitions:**
- **VUS**: A genetic variant where current evidence is insufficient to classify it as patho... | ### Computational Evidence and Gene-Disease Validity Summary for *SHOC2* c.[Variant] (p.Gly349Asp)
**Variant Identification**
The variant under review is located in the *SHOC2* gene, resulting in the protein change p.Gly349Asp (ClinVar ID: 933363; VCV000933363). This variant is currently classified as a Variant of Unc... | VCV000933363 | 31 | Definitive | 933,363 | broader_clingen_entity | SHOC2 | 11 | Tier 1 — highest priority | 5 | 607721 | SHOC2
933363
VCV000933363
ENSP00000358464.5:p.Gly349Asp
11
Tier 1 — highest priority
31.0
5
Noonan syndrome-like disorder with loose anagen hair
Definitive
broader_clingen_entity
607721
40496714
10.1016/j.gimo.2025.103430
2026-06-28
9d381e7918dd | Noonan syndrome-like disorder with loose anagen hair | ENSP00000358464.5:p.Gly349Asp | 9d381e7918dd | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Assess the clinical investigation priority of the following variant identified by the unified RASopathy VUS Series pipeline:
Gene: SOS1
Protein variant: ENSP00000384675.2:p.Arg688Gln
ClinVar ID: 1220476
Investigation score: 13
CADD PHRED: 35.0
Concordant predictors: 4
Clearly explain that Tier 1 represents a computat... | The ENSP00000384675.2:p.Arg688Gln variant (ClinVar ID: 1220476) in SOS1 was classified as Tier 1 — the highest investigation priority — by the unified RASopathy VUS Series pipeline. It received an investigation score of 13, a CADD PHRED score of 35.0, and support from 4 concordant computational predictor(s). Additional... | # Task: Clinical Investigation Priority Assessment
Assess the clinical investigation priority of the variant identified by the unified RASopathy VUS (Variant of Uncertain Significance) Series pipeline using the data provided below.
## Instructions
1. **Analyze the Data**: Review the provided variant details, includin... | # Clinical Investigation Priority Assessment
## Variant Identification
* **Gene:** *SOS1*
* **Protein Change:** ENSP00000384675.2:p.Arg688Gln
* **ClinVar Variation ID:** 1220476 (VCV001220476)
* **Associated Condition:** Noonan syndrome
* **Pipeline Context:** Unified RASopathy VUS Series
## Computational Evidence Pr... | VCV001220476 | 35 | Definitive | 1,220,476 | exact | SOS1 | 13 | Tier 1 — highest priority | 4 | 163950 | SOS1
1220476
VCV001220476
ENSP00000384675.2:p.Arg688Gln
13
Tier 1 — highest priority
35.0
4
Noonan syndrome
Definitive
exact
163950
40496714
10.1016/j.gimo.2025.103430
2026-06-28
29a8c8c334bb | Noonan syndrome | ENSP00000384675.2:p.Arg688Gln | 29a8c8c334bb | 10.1016/j.gimo.2025.103430 | 40496714 | 2026-06-28T00:00:00 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.