ClinVar Miner

Submissions for variant NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val) (rs121908596)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211725 SCV000061254 likely pathogenic Cardio-facio-cutaneous syndrome 2014-11-21 criteria provided, single submitter clinical testing The p.Gly128Val variant in MAP2K1 has been previously identified in 2 individual s with clinical features of Cardio-facio-cutaneous syndrome (Schulz 2008, LMM un published data) and was identified to occur de novo in one of these individuals (Schulz 2008). It was absent from large population studies. Computational predic tion tools and conservation analysis suggest that the p.Gly128Val variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the p.Gly128Val variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207493 SCV000263047 likely pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
GeneDx RCV000207493 SCV000808249 pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing The G128V missense variant in the MAP2K1 gene has been reported previously as de novo and in association with cardiofaciocutaneous syndrome (Schulz et al., 2008). The G128V variant is not observed in large population cohorts (Lek et al., 2016). The G128V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Yet, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Transgenic studies in zebrafish have shown increased pMEK levels and abnormal phenotypic features (Jinal et al., 2017). Missense variants in nearby residues (P124Q/L, Y130H/N/C) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant as pathogenic.
Invitae RCV001234104 SCV001406731 pathogenic Rasopathy 2020-03-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 128 of the MAP2K1 protein (p.Gly128Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID:1804226, 21062266, 18039235, 18413255). In at least one individual the variant has been observed to be de-novo. ClinVar contains an entry for this variant (Variation ID: 13352). This variant has been reported to affect MAP2K1 protein function (PMID:19376813, 28049852). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000043673 SCV000034529 pathogenic Cardiofaciocutaneous syndrome 3 2008-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.