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.199G>A (p.Asp67Asn)

CA180743

40781 (ClinVar)

Gene: MAP2K1

Condition: cardiofaciocutaneous syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8197dee3-bc2e-49dc-88bc-d31b5fd7286f

HGVS expressions

NM_002755.3:c.199G>A

NM_002755.3(MAP2K1):c.199G>A (p.Asp67Asn)

NC_000015.10:g.66435145G>A

CM000677.2:g.66435145G>A

NC_000015.9:g.66727483G>A

CM000677.1:g.66727483G>A

NC_000015.8:g.64514537G>A

NG_008305.1:g.53273G>A

ENST00000307102.9:c.199G>A

ENST00000425818.2:n.710G>A

Pathogenic

PS3 PP3 PP2 PM6_Strong PM2

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.199G>A (p.Asp67Asn) variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17704260). In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390). 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). Computational prediction tools and conservation analysis suggest that the p.Asp67Asn 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): PM6_Strong, PS3, PM2, PP2, PP3.

PS3

In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390).

In vitro functional studies provide some evidence that the p.Asp67Asn variant may impact protein function (PS3; PMID 25049390). PubMed:25049390

PP3

Computational prediction tools and conservation analysis suggest that the p.Asp67Asn variant may impact the protein (PP3).

PP2

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).

PM6_Strong

The p.Asp67Asn variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_S; PMID 17704260).

The p.Asp67Asn variant in MAP2K1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_S; PMID 17704260). PubMed:17704260

PM2

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

Approved on: 2017-05-09

Published on: 2020-01-23

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