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

dbSNP: rs727504370

Total submissions: 6

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)
Labcorp Genetics (formerly Invitae), Labcorp	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