Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_030662.3(MAP2K2):c.383C>A (p.Pro128Gln)

CA279962

8275 (ClinVar)

Gene: MAP2K2
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 307f4b6c-ef49-48bd-98e2-5cf382642800

HGVS expressions

NM_030662.3:c.383C>A
NM_030662.3(MAP2K2):c.383C>A (p.Pro128Gln)
ENST00000262948.9:c.383C>A
ENST00000394867.8:c.92C>A
ENST00000599345.1:n.580C>A
NC_000019.10:g.4110576G>T
CM000681.2:g.4110576G>T
NC_000019.9:g.4110574G>T
CM000681.1:g.4110574G>T
NC_000019.8:g.4061574G>T
NG_007996.1:g.18553C>A

Pathogenic

Met criteria codes 6
PS3 PP1 PP3 PP2 PM1 PM2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.383C>A (p.Pro128Gln) variant in MAP2K2 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 20358587). In vitro functional studies provide some evidence that the p.Pro128Gln variant may impact protein function (PS3; PMID 20358587). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Pro128Gln variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; 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): PP1_Strong, PS3, PM1, PM2, PP2, PP3.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.Pro124Gln variant may impact protein function (PS3; PMID 20358587).
In vitro functional studies provide some evidence that the p.Pro124Gln variant may impact protein function (PS3; PMID 20358587). PubMed:20358587
PP1
The p.Pro124Gln variant in MAP2K2 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_S; 20358587).
PP3
Computational prediction tools and conservation analysis suggest that the p.Pro124Gln variant may impact the protein (PP3).
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2017-05-09
Published on: 2018-12-10
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