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.608A>G

CA234222

167260 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ed63d6b8-8ed7-4649-82e3-855a1228899c

HGVS expressions

NM_002755.3:c.608A>G

NM_002755.3(MAP2K1):c.608A>G

NM_002755.4:c.608A>G

ENST00000307102.9:c.608A>G

ENST00000566326.1:c.80A>G

NC_000015.10:g.66481794A>G

CM000677.2:g.66481794A>G

NC_000015.9:g.66774132A>G

CM000677.1:g.66774132A>G

NC_000015.8:g.64561186A>G

NG_008305.1:g.99922A>G

Pathogenic

PS4_Moderate PP2 PP3 PM6_Strong PM2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.608A>G (p.Glu203Gly) variant in MAP2K1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000965973.1,SCV000202961.7, GeneDx internal data). The variant arose de novo in two of the probands without confirmed parentage (PM6_Strong; SCV000965973.1, SCV000202961.7). Computational prediction tools and conservation analysis suggest that the c.608A>G (p.Glu203Gly) variant may impact protein function (PP3). Finally, the variant is located in MAP2K1, 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). 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, PS4_Moderate, PM2, PP3, PP2.

PS4_Moderate

Observed apparently de novo in an individual with developmental delay and dysmorphic features (SCV000202961.7) Identified in a patient with short stature, dysmorphic features consistent with Noonan syndrome, global developmental delays (GeneDx internal data) 1 patients with Craniofacial phenotype typical, skin excess arose de novo (SCV000965973.1).

PP2

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

PP3

REVEL: 0.785

PM6_Strong

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

PM2

Absent from gnomAD

Approved on: 2020-05-18

Published on: 2020-05-21

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