Submissions for variant NM_000256.3(MYBPC3):c.1471G>A (p.Val491Met)

gnomAD frequency: 0.00001  dbSNP: rs730880543

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158092	SCV000208027	uncertain significance	not provided	2018-10-30	criteria provided, single submitter	clinical testing	The V491M variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM (Coppini et al., 2014; Lopes et al., 2015; Walsh et al., 2017). This variant has been identified in at least two unrelated individuals referred for HCM genetic testing at GeneDx. The V491M variant is observed in 12/111,626 (0.1%) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V491M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, other pathogenic or likely pathogenic variants at a nearby residue (R495G, R495W, R495Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics	RCV000245534	SCV000318274	uncertain significance	Cardiovascular phenotype	2022-10-17	criteria provided, single submitter	clinical testing	The p.V491M variant (also known as c.1471G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1471. The valine at codon 491 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Millat G et al. Clin Chim Acta, 2010 Dec;411:1983-91; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 02;19:192-203; Magrì D et al. J Clin Med, 2020 May;9:[ePub ahead of print]). This amino acid position is well 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454557	SCV000539827	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 patient with HCM. It is present in gnomAD at a Max MAF of 0.01% (12 European alleles). It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (although their blurb suggests VUS) and VUS by Ambry. The variant is not present in Sarcomere Polyphen.
Invitae	RCV000467731	SCV000546451	uncertain significance	Hypertrophic cardiomyopathy	2023-10-03	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 491 of the MYBPC3 protein (p.Val491Met). This variant is present in population databases (rs730880543, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 180940). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000777606	SCV000913473	uncertain significance	Cardiomyopathy	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 491 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 27532257, 32841044, 33495597). This variant has also been identified in 14/249120 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.
Phosphorus, Inc.	RCV000454557	SCV002073394	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of Valine with Methionine at codon 491 of the MYBPC3 gene (transcript: NM_000256.3). This variant has an entry in ClinVar (180940) NM_000256.3(MYBPC3):c.1471G>A (p.Val491Met). This variant occurred in gnomAD with a total MAF of 0 0.0057% and with the highest MAF of 0.0108% in the European population. This position is conserved. In silico functional algorithms predict this variant to be probably damaging (PolyPhen) and deleterious (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has occurred in the literature in association with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 20800588). Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002478476	SCV002776892	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-12-30	criteria provided, single submitter	clinical testing