Submissions for variant NM_000256.3(MYBPC3):c.2269G>A (p.Val757Met)

gnomAD frequency: 0.00001  dbSNP: rs369790992

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766348	SCV000208378	uncertain significance	not provided	2022-01-13	criteria provided, single submitter	clinical testing	Observed in individuals with HCM (Berge et al., 2014; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID #161309); This variant is associated with the following publications: (PMID: 25637381, 23299917, 21415409, 27532257, 28518168, 28679633, 24111713)
Invitae	RCV000463200	SCV000546416	uncertain significance	Hypertrophic cardiomyopathy	2022-05-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 757 of the MYBPC3 protein (p.Val757Met). This variant is present in population databases (rs369790992, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 27532257). ClinVar contains an entry for this variant (Variation ID: 161309). 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: "Probably 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.
Color Diagnostics, LLC DBA Color Health	RCV000777872	SCV000913879	uncertain significance	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 757 of the MYBPC3 protein. Computational prediction indicates that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 27532257). This variant has been identified in 16/249212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002444609	SCV002736611	uncertain significance	Cardiovascular phenotype	2021-07-19	criteria provided, single submitter	clinical testing	The p.V757M variant (also known as c.2269G>A), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2269. The valine at codon 757 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM) genetic testing cohorts; however, limited clinical details were provided (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Whiffin N et al. Genet. Med., 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483290	SCV002784482	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-29	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148680	SCV000190404	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151099	SCV000198862	uncertain significance	not specified	2013-02-12	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000151099	SCV000280234	uncertain significance	not specified	2011-11-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Val757Met in MYBPC3 Given the data reviewed below, we consider it a variant of uncertain significance. This variant has been reported in one case of HCM, online in the Harvard Cardiogenomics Sarcomere Mutation Database, with no clinical information provided (Mark, Seidman et al 2005). This variant has also been reported previously in one Norwegian proband with HCM (Berge and Leren 2014). No further information was provided regarding family segregation. This variant is currently listed in ClinVar, with conflicting assessments of pathogenicity. LMM and the CSER consortium consider this to be a VUS, while GeneDx considers it to be likely disease causing (as of June 23, 2015). This is a conservative amino acid change with a neutral Valine replaced with a neutral Methionine. This variant occurs in the C5 protein domain a region of the MYBPC3 gene which is highly conserved through evolution. There are several other variants in the C5 domain that have been reported in association with HCM (p.Asn755Lys, p.Gly758Asp, p.Asp770Asn, and others). Functional studies of another variant in this region (p.Asn755Lys) indicate that the amino acid change causes thermodynamic instability which leads to complete C5 domain unfolding (Harris et al 2011). In silico analysis (MutationTaster, SIFT) predicts the amino acid change to be damaging to protein structure and function. The variant was not identified in 300 presumably healthy individuals of both Caucasian and African American ancestry at GeneDx. It is is listed in dbSNP: rs369790992. The variant is seen in 8/60,308 individuals of varying ancestries in the ExAC database. All 8 individuals were heterozygous for the p.Val757Met variant and of European descent (as of June 23, 2015).