Variant: NM_030662.4(MAP2K2):c.401A>G (p.Tyr134Cys)

CA180890

177868 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 06d3c00a-69eb-4612-b456-062e6ac0a274

Approved on: 2024-12-03

Published on: 2025-03-31

HGVS expressions

NM_030662.4:c.401A>G
NM_030662.4(MAP2K2):c.401A>G (p.Tyr134Cys)
NC_000019.10:g.4110558T>C
CM000681.2:g.4110558T>C
NC_000019.9:g.4110556T>C
CM000681.1:g.4110556T>C
NC_000019.8:g.4061556T>C
NG_007996.1:g.18571A>G
ENST00000394867.9:n.840A>G
ENST00000687128.1:n.840A>G
ENST00000262948.10:c.401A>G
ENST00000262948.9:c.401A>G
ENST00000394867.8:c.110A>G
ENST00000599345.1:n.598A>G
NM_030662.3:c.401A>G

Likely Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PS3_Supporting PP3 PM1

• Not Met criteria codes: BS1 BS3 BP4 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.401A>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 134 (p.Tyr134Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.966, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 128-138). This variant has been identified in at least 4 patients with RASopathy (PS4_Moderate; PMID: 18413255, 18039235, 21062266, 23885229). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID: 17981815, 18413255). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)

Met criteria codes

• PS4_Moderate: This variant has been identified in at least 4 patients with RASopathy (PMID: 18413255, 18039235, 21062266, 23885229).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1
• PS3_Supporting: ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Moderate; PMID: 17981815, 18413255)
• PP3: The computational predictor REVEL gives a score of 0.966, predicting a damaging impact on protein function
• PM1: This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 128-138)

Not Met criteria codes

• BS1: This variant is absent from gnomAD v2.1.1
• BS3: In vitro functional studies provide some evidence that the p.Tyr134Cys variant may impact protein function
• BP4: The computational predictor REVEL gives a score of 0.966, predicting a damaging impact on protein function
• BA1: This variant is absent from gnomAD v2.1.1