ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2429G>T (p.Arg810Leu) (rs375675796)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158444 SCV000208379 likely pathogenic not provided 2017-01-26 criteria provided, single submitter clinical testing The R810L likely pathogenic variant in the MYBPC3 gene has been previously published in association with HCM (Millat et al., 2010; Olivotto et al., 2011). Millat et al. (2010) originally reported R810L in an individual with HCM who also harbored a second variant (R1022P) in the MYBPC3 gene. Olivotto et al. (2011) identified R810L independently in an individual with HCM. The R810L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R810L 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, a missense variant in the same residue (R810H) and missense variants in nearby residues (G805S, I807N, K811R) have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.
Invitae RCV000458102 SCV000546461 uncertain significance Hypertrophic cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 810 of the MYBPC3 protein (p.Arg810Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 21835320, 20624503, 20800588); however, one of the affected individuals carried another pathogenic variant in MYBPC3 which suggests that this c.2429G>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 181127). 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. In summary this is a rare variant that has been reported in individuals with HCM and has un uncertain effect on MYBPC3 protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000617694 SCV000739949 likely pathogenic Cardiovascular phenotype 2018-02-13 criteria provided, single submitter clinical testing The p.R810L variant (also known as c.2429G>T), located in coding exon 25 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 2429. The arginine at codon 810 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in several unrelated individuals with hypertrophic cardiomyopathy (HCM), although in one case other alterations were also detected (Millat G et al. Eur J Med Genet 2010 Jul; 53(5):261-7; Olivotto I et al. J. Am. Coll. Cardiol. 2011 Aug; 58(8):839-48). Additionally, another variant affecting the same amino acid, p.R810H (c.2429G>A), has also been identified in multiple HCM cases, though some individuals were positive for other cardiac variants as well (Nanni et al. Biochem Biophys Res Commun. 2003;309(2):391-8; Maron et al. Am J Cardiol. 2011;107(4):604-8; Roncarati et al. Cell Physiol. 2011;226(11):2894-900). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627129 SCV000747941 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-06-16 criteria provided, single submitter clinical testing

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