ClinVar Miner

Submissions for variant NM_030662.3(MAP2K2):c.401A>G (p.Tyr134Cys) (rs727504370)

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Total submissions: 5
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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, 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, Partners HealthCare 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 2015-05-22 criteria provided, single submitter clinical testing TheY134C missense variant in the MAP2K2 gene has been reported previously in association with Cardio-facio-cutaneous syndrome (CFC) (Rodriguez-Viciana et al., 2008). The Y134C variant occurs in the conserved protein kinase domain of MAP2K2. Additionally, a missense variant in the same residue (Y134H) and variants in nearby residues (G132V, G132D) have been reported in the Human Gene Mutation Database in association with CFC (Stenson et al., 2014), supporting the functional importance of this region of the protein. The Y134C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The presence of this variant is consistent with a diagnosis of a Noonan-related disorder
Invitae RCV000154507 SCV000551456 likely pathogenic Rasopathy 2016-09-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 134 of the MAP2K2 protein (p.Tyr134Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (rs727504370, ExAC no frequency). This variant has been reported in individuals with cardio-facio-cutaneous syndrome (PMID: 18413255, 18039235, 23885229). This variant is also known as MEK2 Y134C in the literature. ClinVar contains an entry for this variant (Variation ID: 177868). Experimental studies have shown that this missense change leads to increased MEK activity and ERK phosphorylation (PMID: 18413255, 19376813, 17981815). In summary, this missense change has been reported in affected individuals and leads to increased protein activity. While this variant is likely to be pathogenic, additional genetic data is needed to prove that conclusively. Therefore, it has been classified as Likely Pathogenic.
GeneReviews RCV000208747 SCV000264643 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only

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