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

CA296157

40842 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

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

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

• Met criteria codes: BP5 PP2

• Not Met criteria codes: BS1 BS4 BP4 PS1 PS4 PM5 PM1 PM2 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

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.

Met criteria codes

• BP5: Invitae internal data includes 1 proband (teenaged female) with syncope and atrial fibrillation who has a pathogenic variant in a cardiomyopathy gene
• PP2: MAP2K is a missense-constrained gene

Not Met criteria codes

• 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.
• 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.
• PM5: One other variant reported in ClinVar, but VUS.
• PM1: Mutation does not occur within residues 47-65 or 128-38.
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-08-26

Published on: 2019-10-02