ClinVar Miner

Submissions for variant NM_030662.4(MAP2K2):c.401A>G (p.Tyr134Cys)

dbSNP: rs727504370
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000208747 SCV000616541 pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation The c.401A>G (p.Tyr134Cys) variant in MAP2K2 has been identified in one patient with clinical features of a RASopathy (PMID 18413255). In vitro functional studies provide some evidence that the p.Tyr134Cys variant may impact protein function (PS3; PMID 18413255). 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). 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). Computational prediction tools and conservation analysis suggest that the p.Tyr134Cys 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): PS3, PM2, PM1, PP2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000844676 SCV000204178 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2018-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000412815 SCV000490999 pathogenic not provided 2022-07-22 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect in which the variant causes increased kinase activity and activation of downstream effectors (MEK and ERK), indicating a gain of function (Rodriguez-Viciana et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 29752777, 25370473, 22753777, 19156172, 26399658, 22177953, 29493581, 18042262, 18413255)
Invitae RCV000154507 SCV000551456 pathogenic RASopathy 2022-06-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MAP2K2 function (PMID: 17981815, 18413255, 19376813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 177868). This variant is also known as MEK2 Y134C. This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (PMID: 18039235, 18413255, 23885229). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MAP2K2 protein (p.Tyr134Cys).
GeneReviews RCV000208747 SCV000264643 not provided Cardio-facio-cutaneous syndrome no assertion provided literature only
Molecular Genetics, Centre for Human Genetics RCV003453160 SCV004190079 pathogenic Noonan syndrome 1 no assertion criteria provided clinical testing

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