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.323G>T (p.Arg108Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10603467

280446 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 33491ca8-e49c-4685-80a6-287992b87237

Approved on: 2020-06-25

Published on: 2020-07-01

HGVS expressions

NM_002755.3:c.323G>T

NM_002755.3(MAP2K1):c.323G>T (p.Arg108Leu)

NM_002755.4:c.323G>T

ENST00000307102.9:c.323G>T

ENST00000425818.2:n.834G>T

NC_000015.10:g.66436777G>T

CM000677.2:g.66436777G>T

NC_000015.9:g.66729115G>T

CM000677.1:g.66729115G>T

NC_000015.8:g.64516169G>T

NG_008305.1:g.54905G>T

Pathogenic

PS2 PP2 PP3 PM2 PM6

PM5 PM1

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.323G>T (p.Arg108Leu) variant in MAP2K1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in 2 probands, one of whom had maternity and paternity confirmed (PS2, PM6; Fulgent Genetics and Baylor Genetics internal data, ClinVar SCV000894927.1). 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.Arg108Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PM2, PM6, PP2, PP3.

PS2

Observed in 1 de novo occurrence with parental confirmation (Fulgent Genetics internal data).

PP2

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

PP3

REVEL 0.831. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing.

PM2

Absent from both versions of gnomAD.

PM6

Observed in 1 de novo occurrence without parental confirmation (Baylor Genetics internal data).

PM5

2 other variants at this codon: 1 LB (Trp), 1 VUS (Gln).

PM1

Does not occur between amino acids 43-61 or 124-134.

Curation History

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