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.275T>G (p.Leu92Arg)

CA134601

44588 (ClinVar)

Gene: MAP2K1

Condition: cardiofaciocutaneous syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2986f8eb-3ee8-416d-a279-f72ff1c134a1

HGVS expressions

NM_002755.3:c.275T>G

NM_002755.3(MAP2K1):c.275T>G (p.Leu92Arg)

NM_002755.4:c.275T>G

ENST00000307102.9:c.275T>G

ENST00000425818.2:n.786T>G

NC_000015.10:g.66435221T>G

CM000677.2:g.66435221T>G

NC_000015.9:g.66727559T>G

CM000677.1:g.66727559T>G

NC_000015.8:g.64514613T>G

NG_008305.1:g.53349T>G

Pathogenic

PS2_Very Strong PS4_Moderate PP3 PP2 PM2

PM6

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.275T>G (p.Leu92Arg) variant in MAP2K1 has been reported in at least 3 de novo occurrences, including 1 case with parental confirmation, in patients diagnosed with a RASopathy (PS2_VeryStrong, PS4_Moderate; GeneDx, APHP-Robert Debre hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5). This variant was absent from large population studies (PM2; gnomad.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.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, PS4_Moderate, PM2, PP2, PP3.

PS2_Very Strong

Reported in at least 3 de novo occurrences, including 1 case with parental confirmation, in patients diagnosed with a RASopathy (PS2_VeryStrong, PS4_Moderate; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5).

PS4_Moderate

PP3

Computational prediction tools and conservation analysis suggest that the p.Leu92Arg 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).

PM2

Absent from both versions of gnomAD.

PM6

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

Approved on: 2020-06-25

Published on: 2020-07-01

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