Submissions for variant NM_000256.3(MYBPC3):c.787G>A (p.Gly263Arg) (rs373730381)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412865	SCV000490635	uncertain significance	not provided	2016-05-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The Gly263Arg variant has been reported as a de novo variant in one patient with HCM and was absent from 120 control individuals; however, functional studies and detailed clinical information were not provided. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project10, indicating it is not a common benign variant in these populations. The Gly263Arg 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. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae	RCV000528899	SCV000623621	uncertain significance	Hypertrophic cardiomyopathy	2018-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 263 of the MYBPC3 protein (p.Gly263Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs373730381, ExAC 0.2%). This variant has been observed to be de novo in an individual affected with hypertrophic cardiomyopathy (PMID: 15563892). ClinVar contains an entry for this variant (Variation ID: 161315). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV000617282	SCV000740241	uncertain significance	Cardiovascular phenotype	2017-10-20	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000770378	SCV000901819	uncertain significance	Cardiomyopathy	2017-06-02	criteria provided, single submitter	clinical testing
CSER_CC_NCGL; University of Washington Medical Center	RCV000148690	SCV000190417	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research