Evidence Repository - Clinical Genome Resources

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_002755.3(MAP2K1):c.370C>T (p.Pro124Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16602456

375981 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5725ca85-ac7d-4884-bdcb-d5ee4a24cee6

Approved on: 2020-07-02

Published on: 2020-07-02

HGVS expressions

NM_002755.3:c.370C>T

NM_002755.3(MAP2K1):c.370C>T (p.Pro124Ser)

NM_002755.4:c.370C>T

ENST00000307102.9:c.370C>T

ENST00000425818.2:n.881C>T

NC_000015.10:g.66436824C>T

CM000677.2:g.66436824C>T

NC_000015.9:g.66729162C>T

CM000677.1:g.66729162C>T

NC_000015.8:g.64516216C>T

NG_008305.1:g.54952C>T

Pathogenic

PS3 PP2 PP3 PM1 PM2 PS2_Very Strong

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.370C>T (p.Pro124Ser) variant in MAP2K1 has been observed as a de novo occurrence with maternity and paternity confirmed in 2 probands with features of a RASopathy (PS2_VeryStrong; GeneDx internal data, ClinVar SCV000572401.5). In vitro functional studies provide some evidence that the p.Pro124Ser variant may impact protein function (PS3; PMID: 22197931). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Pro124Ser variant is located in the MAP2K1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Leu92Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS2_VeryStrong, PS3, PM1, PM2, PP2, PP3.

PS3

Compared to WT MAP2K1, the P124S variant caused increased phosphorylation of ERK1/2 in HEK293T cells. BRAFV600E was used as a positive control.

Compared to WT MAP2K1, the P124S variant caused increased phosphorylation of ERK1/2 in HEK293T cells. BRAFV600E was used as a positive control. PubMed:22197931

PP2

MAP2K1 is a missense-constrained gene (PMID: 29493581).

PP3

REVEL 0.855. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing.

PM1

Falls between amino acids 124 and 134 (PMID: 29493581).

PM2

Absent from both versions of gnomAD.

PS2_Very Strong

Observed in 2 de novo cases with parental confirmation.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.