Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_030662.4(MAP2K2):c.400T>C (p.Tyr134His)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA119417

8274 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b513b1fc-147c-4877-bb0a-38f55e252576

Approved on: 2024-12-03

Published on: 2025-03-31

HGVS expressions

NM_030662.4:c.400T>C

NM_030662.4(MAP2K2):c.400T>C (p.Tyr134His)

NC_000019.10:g.4110559A>G

CM000681.2:g.4110559A>G

NC_000019.9:g.4110557A>G

CM000681.1:g.4110557A>G

NC_000019.8:g.4061557A>G

NG_007996.1:g.18570T>C

ENST00000394867.9:n.839T>C

ENST00000687128.1:n.839T>C

ENST00000262948.10:c.400T>C

ENST00000262948.9:c.400T>C

ENST00000394867.8:c.109T>C

ENST00000599345.1:n.597T>C

NM_030662.3:c.400T>C

Pathogenic

PS3_Supporting PP3 PM1 PM2_Supporting PM6_Strong PS4

BA1 PM5 BS1 BP4

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.400T>C variant in the MAP2K2 gene is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 134 (p.Tyr134His). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.917, 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). Furthermore, a different pathogenic variant at this residue (Tyr134Cys) has been identified in several patients with RASopathies (PM5). This variant has been identified in at least 6 patients with a RASopathy, of which 2 were unconfirmed de novo cases (PS4, PM6_Strong; Partners LMM, Labcorp internal data, ClinVar: SCV000063166.5, SCV002210187.3; PMID: 18042262, 18456719, 27763634). Western blot assay in Ba/F3 cells showed that the variant activated ERK signaling while the wildtype did not (PS3_Supporting, PMID: 30867592). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4, PM6_Strong, PM1, PM5, PS3_Supprting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)

PS3_Supporting

Western blot assay in Ba/F3 cells showed that MEK2 Y134H mutant activated ERK signaling while WT did not (PMID: 30867592)

PP3

The computational predictor REVEL gives a score of 0.917, 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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1

PM6_Strong

This variant was reported as a de novo occurrence in 2 probands (Labcorp, ClinVar SCV002210187.3; PMID: 18456719)

PS4

This variant has been identified in at least 6 patients with a RASopathy (Partners LMM, Labcorp internal data, ClinVar: SCV000063166.5, SCV002210187.3; PMID: 18042262, 18456719, 27763634)

BA1

This variant is absent from gnomAD v2.1.1

PM5

A different pathogenic missense variant has been previously identified at this codon of MAP2K2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 177868). Cannot be applied in conjunction with PM1

BS1

This variant is absent from gnomAD v2.1.1

BP4

The computational predictor REVEL gives a score of 0.917, predicting a damaging impact on protein function

Curation History

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