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

  • See Evidence submitted by expert panel for details.

Variant: NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys)

CA280036

13351 (ClinVar)

Gene: MAP2K1
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 1eaf4dad-ab0c-49ae-8548-22bad4210249
Approved on: 2017-05-09
Published on: 2018-12-10

HGVS expressions

NM_002755.3:c.389A>G
NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys)
ENST00000307102.9:c.389A>G
ENST00000425818.2:n.900A>G
NC_000015.10:g.66436843A>G
CM000677.2:g.66436843A>G
NC_000015.9:g.66729181A>G
CM000677.1:g.66729181A>G
NC_000015.8:g.64516235A>G
NG_008305.1:g.54971A>G
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Pathogenic

Met criteria codes 6
PS3 PP3 PP2 PM2 PM1 PS2_Very Strong

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.389A>G (p.Tyr130Cys) variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStong; PMID 16439621, 17551924, 18042262). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). 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 MAP2K1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr130Cys variant may impact the protein (PP3). 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): PS2_VeryStrong, PP3, PS3, PM2, PP2, PM1.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).

PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
The variant is in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581)
PM2
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 MAP2K1 (PM1; PMID 29493581)
PS2_Very Strong
The p.Tyr130Cys variant in MAP2K1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VS; PMID 16439621, 17551924, 18042262).

Curation History
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