Submissions for variant NM_002755.4(MAP2K1):c.169A>C (p.Lys57Gln)

dbSNP: rs397516790

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000158014	SCV000616537	likely pathogenic	RASopathy	2017-05-09	reviewed by expert panel	curation	The c.169A>C (p.Lys57Gln) 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; Partners LMM GeneDx internal data 26957, 21766; ClinVar SCV000061249.5; SCV000207949.2). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Lys57Gln variant may impact the protein (PP3). 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). 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, PM2, PP3, PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037591	SCV000061249	likely pathogenic	Cardio-facio-cutaneous syndrome	2016-02-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158014	SCV000207949	likely pathogenic	RASopathy	2019-02-14	criteria provided, single submitter	clinical testing	To our knowledge, this variant has neither been published as a Pathogenic variant, nor has it been reported as a benign polymorphism. The K57Q missense change is considered to be a non-conservative amino acid substitution, as a positively charged residue (Lys) is replaced by a neutral residue (Gln) at a position in the protein that is highly conserved across species and within related proteins. Furthermore, missense changes in nearby codons (F53S and T55P) have previously been reported in association with cardio-facio-cutaneous syndrome and Costello syndrome, respectively, which are other disorders of the RAS/MAPK pathway (Rodriguez - Viciana et al., 2006; Nava et al., 2007). Therefore, K57Q is considered to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000158014	SCV001568953	uncertain significance	RASopathy	2018-06-24	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change causes increased downstream phosphorylation of ERK (PMID: 18632602). This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40779). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 57 of the MAP2K1 protein (p.Lys57Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine.