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_030662.3(MAP2K2):c.1112G>A (p.Arg371Gln)

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Curation History
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CA296157

40842 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 58e61181-b2bb-4f50-9d9a-4c506757fc9d

Approved on: 2019-08-26

Published on: 2019-10-02

HGVS expressions

NM_030662.3:c.1112G>A

NM_030662.3(MAP2K2):c.1112G>A (p.Arg371Gln)

NC_000019.10:g.4090689C>T

CM000681.2:g.4090689C>T

NC_000019.9:g.4090687C>T

CM000681.1:g.4090687C>T

NC_000019.8:g.4041687C>T

NG_007996.1:g.38440G>A

ENST00000262948.9:c.1112G>A

ENST00000394867.8:c.821G>A

ENST00000597263.5:n.297G>A

ENST00000599021.1:n.222G>A

ENST00000600584.5:n.2561G>A

ENST00000601786.5:n.1413G>A

Uncertain Significance

PP2 BP5

PS1 PS4 PM2 PM5 PM1 BA1 BS1 BS4 BP4

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The p.Arg371Gln variant in MAP2K2 has been identified in 0.00401% (lower bound of the 95% CI of 7/81796) of non-Finnish European chromosomes in gnomAD (https://gnomad.broadinstitute.org) (BS1 not met). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The variant is located in the MAP2K2 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). This variant has been observed in many individuals with varying clnical presentations that lack clear associations with a RASopathy. This variant was identified in 1 individual with syncope and atrial fibrillation, who carried an additional pathogenic variant in a cardiomyopathy gene sufficient to explain their clinical presentation (BP5; Invitae internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP2, BP5.

PP2

MAP2K is a missense-constrained gene

BP5

Invitae internal data includes 1 proband (teenaged female) with syncope and atrial fibrillation who has a pathogenic variant in a cardiomyopathy gene

PS1

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

PS4

Internal data from Invitae includes 4 patients with this variant: 1 teenaged female with syncope and atrial fibrillation who had a pathogenic variant in a cardiomyopathy gene, 1 infant female with widely spaced nipples and posterior neck fold, 1 male in his 50's with HCM, and 1 female in her 30's with tricuspid atresia. 1 proband from Bhoj et al. Integrated internal data: seen in the heterozygous state in 2 probands without other clinical information. GeneDx classified as LB based on frequency, in silico predictors, and failure to segregate with phenotype in 1 family (did not specify phenotype). None of these cases were counted due to inconsistent phenotypes.

1 undiagnosed 15y old patient with BSNL, short stature, short and broad thumbs and first toes, and slightly low-set ears. Tested for 10 other genes PubMed:27763634

PM2

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

PM5

One other variant reported in ClinVar, but VUS.

PM1

Mutation does not occur within residues 47-65 or 128-38.

BA1

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

BS1

Identified in 0.00401% (lower bound of the 95% CI of 7/81796) of non-Finnish European chromosomes in gnomAD

BS4

GeneDx reports 1 failure to segregate, but does not provide phenotype

BP4

No impact to splicing. REVEL score 0.341. No other mammals have Gln at this site.

Curation History

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