Submissions for variant NM_000256.3(MYBPC3):c.1595G>T (p.Gly532Val)

dbSNP: rs730880547

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158102	SCV000208037	uncertain significance	not provided	2013-04-24	criteria provided, single submitter	clinical testing	p.Gly532Val (GGC>GTC): c.1595 G>T in exon 17 of the MYBPC3 gene (NM_000256.3)The Gly532Val variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Gly532Val variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although Gly532Val results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is well conserved across species. However, nearby residues in this region are not well conserved. Nevertheless, mutations in nearby residues (Gly523Arg, Gly523Trp, Tyr525Ser, Gly531Arg, Glu542Gln) have been reported in association with HCM, supporting the functional importance of this region of the proten. In silico algorithms are not consistent in their predictions; one algorithm predicts Gly532Val is damaging to the protein structure/function, while another predicts Gly532Val is tolerated.With the clinical and molecular information available at this time, we cannot definitively determine if Gly532Val is a disease-causing mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857559	SCV002282080	uncertain significance	Hypertrophic cardiomyopathy	2021-03-31	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces glycine with valine at codon 532 of the MYBPC3 protein (p.Gly532Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 180944). 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.