ClinVar Miner

Submissions for variant NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys) (rs121908595)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623321 SCV000740780 pathogenic Inborn genetic diseases 2015-01-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000043672 SCV000807282 pathogenic Cardiofaciocutaneous syndrome 3 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 13-year-old female with autistic features, absent speech, epilepsy, coarse features, ptosis, left mesial temporal sclerosis
ClinGen RASopathy Variant Curation Expert Panel RCV000208757 SCV000616532 pathogenic Cardio-facio-cutaneous syndrome 2017-05-09 reviewed by expert panel curation 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.
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000043672 SCV000236502 pathogenic Cardiofaciocutaneous syndrome 3 2013-12-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000207506 SCV000341853 pathogenic not provided 2016-05-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763362 SCV000894053 pathogenic Noonan syndrome 1; Cardiofaciocutaneous syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000207506 SCV000207943 pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing The Y130C pathogenic variant in the MAP2K1 gene has been reported previously in individuals with cardio-faciocutaneous syndrome (Rodriguez-Viciana et al., 2006; Rodriguez-Viciana et al., 2008; Celik et al., 2014). Functional in vitro studies have demonstrated that Y130C results in increased kinase activity and activation of downstream effectors (MEK and ERK), indicating a gain of function effect (Rodriguez-Viciana et al., 2008). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y130C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at the same residue (Y130N/H) and in a nearby residue (G128V) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
GeneReviews RCV000208757 SCV000264638 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000208757 SCV000698036 pathogenic Cardio-facio-cutaneous syndrome 2016-04-26 criteria provided, single submitter clinical testing Variant summary: The c.389A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant. This variant is not found in approximately 121830 control chromosomes. The variant has been reported in several CFC patients including multiple confirmed de novo occurrences, a very strong evidence for pathogenic outcome. A functional study by Rodriguez-Viciana et al 2006 also showed the variant to have an activating effect on ERK phosphorylation, consistent with disease mechanism in CFC. Several clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic.
Invitae RCV000541525 SCV000659027 pathogenic Rasopathy 2017-07-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 130 of the MAP2K1 protein (p.Tyr130Cys). 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 (ExAC no frequency). This variant has been reported in many individuals affected with cardio-facio-cutaneous syndrome (PMID: 16439621, 17366577, 17551924, 18413255, 18854871, 24637312). In most of these individuals, the variant was shown to be de novo. It has also been reported in individuals who presented with unclassified epilepsy (PMID: 26795593) and intellectual disability (PMID: 26350204). This gene is also called MEK1 in the literature. ClinVar contains an entry for this variant (Variation ID: 13351). Experimental studies have shown that this missense change results in increased MAP2K1 kinase activity (PMID: 16439621, 18413255, 19376813). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208757 SCV000061256 pathogenic Cardio-facio-cutaneous syndrome 2016-08-30 criteria provided, single submitter clinical testing The p.Tyr130Cys variant in MAP2K1 has been reported in >15 individuals with clin ical features of Cardio-facio-cutaneous (CFC) syndrome and occurred de novo in a t least 10 individuals (Rodriguez-Viciana 2006, Gripp 2007, Narumi 2007, Schulz 2008, Dentici 2009, LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that this variant may im pact protein function (Rodriguez-Viciana 2006). Computational prediction tools a nd conservation analysis suggest that the p.Tyr130Cys variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, this variant meets criteria to be classified as pathogenic for CF C in an autosomal dominant manner based on multiple de novo occurrences and abse nce from controls.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207506 SCV000263049 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
OMIM RCV000043672 SCV000034528 pathogenic Cardiofaciocutaneous syndrome 3 2006-03-03 no assertion criteria provided literature only

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