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]

Link to SEPIO compliant JSON-LD document

Variant: NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys)

CA280036

13351 (ClinVar)

Gene: MAP2K1

Condition: cardiofaciocutaneous syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1eaf4dad-ab0c-49ae-8548-22bad4210249

HGVS expressions

NM_002755.3:c.389A>G

NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys)

ENST00000307102.9:c.389A>G

ENST00000425818.2:n.900A>G

NC_000015.10:g.66436843A>G

CM000677.2:g.66436843A>G

NC_000015.9:g.66729181A>G

CM000677.1:g.66729181A>G

NC_000015.8:g.64516235A>G

NG_008305.1:g.54971A>G

Pathogenic

PM2 PM1 PS2_Very Strong PS3 PP3 PP2

Evidence Links 6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.389A>G (p.Tyr130Cys) variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStong; PMID 16439621, 17551924, 18042262). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The 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.Tyr130Cys 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, PP3, PS3, PM2, PP2, PM1.

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

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)

PS2_Very Strong

The p.Tyr130Cys variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VS; PMID 16439621, 17551924, 18042262).

The p.Tyr130Cys variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VS; PMID 16439621, 17551924, 18042262). PubMed:16439621

PS3

In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).

In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). PubMed:18413255

In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). PubMed:17981815

In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). PubMed:23093928

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP2

The variant is in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581)

Approved on: 2017-05-09

Published on: 2018-12-10

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