Submissions for variant NM_000256.3(MYBPC3):c.745T>C (p.Cys249Arg)

gnomAD frequency: 0.00001  dbSNP: rs397516071

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035664	SCV000059315	uncertain significance	not specified	2015-05-16	criteria provided, single submitter	clinical testing	The p.Cys249Arg variant in MYBPC3 has been identified by our laboratory in 1 Afr ican American individual with DCM. It has also been identified in 1/8044 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs397516071). Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact to the protein. In s ummary, the clinical significance of the p.Cys249Arg variant is uncertain.
Ambry Genetics	RCV000241606	SCV000320420	uncertain significance	Cardiovascular phenotype	2022-12-27	criteria provided, single submitter	clinical testing	The p.C249R variant (also known as c.745T>C), located in coding exon 6 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 745. The cysteine at codon 249 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Pugh TJ et al. Genet Med. 2014;16(8):601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001205568	SCV001376830	uncertain significance	Hypertrophic cardiomyopathy	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 249 of the MYBPC3 protein (p.Cys249Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs397516071, ExAC 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42788). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
GeneDx	RCV001762112	SCV001989064	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Reported in association with DCM, although no clinical or segregation data were provided (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42788; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)