Submissions for variant NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly)

dbSNP: rs397515905

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000466543	SCV000059051	likely pathogenic	Hypertrophic cardiomyopathy	2017-02-06	criteria provided, single submitter	clinical testing	The p.Arg495Gly variant in MYBPC3 has been identified in 7 individuals with HCM (Morita 2008, Frisso 2009, Millat 2010, Calore 2015, LMM data), including 2 who also carried an additional disease-causing variant, and has also been reported b y other clinical laboratories in ClinVar (Variation ID: 42537). This variant seg regated with disease in 3 affected family members from 2 families (Frisso 2009, LMM data). However, this variant did not segregate with disease in all families (Morita 2008). It has been identified in 1/111690 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515 905). In addition, two different amino acid changes at this position (p.Arg495Tr p and p.Arg495Gln) have been reported in individuals with HCM (Niimura 1998, Mar on 2001, Garcia-Castro 2009, Martin 2009, Rodriguez-Garcia 2010, Brito 2012, Cot o 2012, Lopes 2013), suggesting that changes at this position are not tolerated. However, data suggests that the p.Arg495Gln variant may have reduced penetrance . Computational prediction tools and conservation analysis suggest that this var iant may impact the protein. In summary, although additional studies are require d to fully establish its clinical significance, the p.Arg495Gly variant is likel y pathogenic. ACMG/AMP criteria applied (Richards 2015): PS4_Moderate, PM2, PP1, PP3.
GeneDx	RCV000158093	SCV000208028	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19659763, 22574137, 26671970, 31006259, 20019025, 23140321, 23396983, 22267749, 18403758, 24704860, 20624503, 23690394, 20433692, 9562578, 18713777, 19150014, 11499718, 28615295, 25611685, 25740977, 25031304, 21415409, 25058872, 22857948, 22765922, 27532257, 28408708, 31447099, 31589614, 33012304, 33087929, 34400558)
Invitae	RCV000466543	SCV000546465	pathogenic	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 495 of the MYBPC3 protein (p.Arg495Gly). This variant is present in population databases (rs397515905, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 20624503, 22574137). ClinVar contains an entry for this variant (Variation ID: 42537). 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. This variant disrupts the p.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9562578, 19150014, 20433692, 22765922, 23396983, 26671970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584783	SCV000692510	pathogenic	Hypertrophic cardiomyopathy 1	2017-03-14	criteria provided, single submitter	research	This MYBPC3 Arg495Gly variant has previously been identified in multiple unrelated HCM cases and absent from >1500 control chromosomes, collectively (Alfares AA, et al., 2015; Morita H, et al., 2008; Frisso G, et al., 2009; Millat G, et al., 2010; Calore C, et al., 2015; Oxford genetics, https://cardiodb.org.uk/ACGV/acgv_variant.php?id=4185). This variant is also absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Familial evaluation by Page SP, et al. (2012) identified Arg495Gly in 3 affected HCM cases (2 families) with fully penetrant disease. Similarly, Frisso G, et al. (2009) found the MYBPC3 Arg495Gly variant in 2 affected family members albeit with different disease phenotypes - one individual was diagnosed with childhood HCM, and his father with LVNC. Incomplete penetrance and/or asymptomatic carriers of this variant has been reported in the literature where familial screening is available (Christiaans I, et al., 2010; Morita H, et al., 2008). We identified this variant in 1 HCM proband with a family history of disease, however segregation was not possible. Interestingly, other amino acid substitutions at codon 495 (Arg495Trp, Arg495Gln) have also been idenitifed in HCM cases, and the Arg495Gln variant has been classified as a pathogenic variant, which provides strong support that that an amino acid substitution at this position is not tolerated. Structurally, Arg495 is located in a positively charged region of the C3 domain, where it is exposed on the protein surface of MYBPC3. It is predicted that amino acid substitutions in this domain will likely perturb the surface charge and disrupt the interaction of MYBPC3 with other proteins (Zhang XL, et al., 2014). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict MYBPC3 Arg495Gly to be disease-causing. In summary, based on rarity in general populations, reports of multiple HCM probands with the variant, segregation data and the pathogenic classification of a different amino acid substitution at this position, we classify the MYBPC3 Arg495Gly variant as "pathogenic".
Ambry Genetics	RCV000620109	SCV000736858	pathogenic	Cardiovascular phenotype	2021-06-10	criteria provided, single submitter	clinical testing	The p.R495G pathogenic mutation (also known as c.1483C>G), located in coding exon 17 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 1483. The arginine at codon 495 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been detected in multiple unrelated individuals reported to have hypertrophic cardiomyopathy (HCM) (Morita HN et al. Engl J Med. 2008;358(18):1899-908; Millat G et al. Eur J Med Genet. 2010;53:261-7; Teirlinck CH et al. BMC Med Genet. 2012;13:105; Calore C et al. J Med Genet. 2015;52:338-47; Lopes LR et al. Heart. 2015;101(4):294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]). This alteration has also been described in individuals having HCM with non-compaction or dilated-phase HCM (Frisso G et al. Clin Genet. 2009;76(1):91-101; Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66). Furthermore, two other alterations affecting this amino acid (p.R495Q, c.1484G>A and p.R495W, c.1483C>T) have also been reported in association with HCM (García-Castro M et al. Rev Esp Cardiol. 2009 Jan;62(1):48-56; Helms AS. Circ Cardiovasc Genet. 2014 Aug;7(4):434-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001187169	SCV001353884	likely pathogenic	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 495 in the Ig-like domain C3 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: 18403758, 19659763, 20624503, 22267749, 22574137, 23140321, 25611685, 26455666, 27532257, 28615295, 34310159). Different variants occurring at the same codon, p.Arg495Gln and p.Arg495Trp, are well documented pathogenic mutations (Clinvar variation ID: 164113 and 164114), indicating that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 1/249206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000158093	SCV003828477	likely pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing