Submissions for variant NM_002755.4(MAP2K1):c.388T>C (p.Tyr130His)

dbSNP: rs397516793

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000037596	SCV000616533	likely pathogenic	Cardio-facio-cutaneous syndrome	2017-05-09	reviewed by expert panel	curation	The c.388T>C (p.Tyr130His) variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19156172). 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). A different pathogenic missense variant has been previously identified at this codon of MAP2K1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13351). 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PM1, PP3, PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037596	SCV000061255	pathogenic	Cardio-facio-cutaneous syndrome	2012-03-07	criteria provided, single submitter	clinical testing	The Tyr130His variant has been reported in one individual with clinical features of Cardio-facio-cutaneous syndrome and was shown to have occurred de novo (Dent ici 2009). In addition, Tyr130Cys and Tyr130Asn have been reported in several i ndividuals with CFC and tyrosine at position 130 represents the most commonly mu tated amino acid in MEK1 (Gripp 2007, Rodriguez-Viciana 2006, Dentici 2009, Naru mi 2007, Schulz 2008). In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM). The presence of a heterozygo us pathogenic variant in MEK1 is consistent with a diagnosis of cardio-facio-cut aneous syndrome but this information should be reconciled with the complete clin ical history of this individual.
Ambry Genetics	RCV000623628	SCV000740998	pathogenic	Inborn genetic diseases	2015-07-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811234	SCV001473272	pathogenic	not provided	2019-09-12	criteria provided, single submitter	clinical testing	The MAP2K1 c.388T>C; p.Tyr130His variant (rs397516793) is reported in the literature in individuals affected with cardio-facio-cutaneous (CFC) syndrome, including at least one de novo occurence (Dentici 2009). This variant is reported in ClinVar (Variation ID: 40747), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 130is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, tyrosine 130 is considered a mutational hotspot (Bromberg-White 2012), and other variants at this codon (c.389A>G; p.Tyr130Cys, c.388T>A; p.Tyr130Asn) have been reported in individuals with CFC syndrome and are considered pathogenic (Dentici 2009, Gripp 2007, Rodriguez-Viciana 2008). In vitro functional analyses demonstrate that the p.Tyr130His variant leads to overactivation of the MAP2K1 protein (Hao 2008). Based on available information, the p.Tyr130His variant is considered to be pathogenic. References: Bromberg-White JL et al. MEK genomics in development and disease. Brief Funct Genomics. 2012 Jul;11(4):300-10. Dentici ML et al. Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. Eur J Hum Genet. 2009 Jun;17(6):733-40. Gripp KW et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007 Jul 1;143A(13):1472-80. Hao YH et al. Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways. PLoS One. 2008 Jan 2;3(1):e1375. Rodriguez-Viciana P and Rauen KA. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89.