ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1483C>G (p.Arg495Gly) (rs397515905)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584783 SCV000692510 pathogenic Familial 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 2018-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
GeneDx RCV000158093 SCV000208028 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The R495G pathogenic variant in the MYBPC3 gene has been reported previously in multiple individuals with HCM (Morita et al., 2008; Frisso et al., 2009; Christiaans et al., 2010; Millat et al., 2010; Page et al. 2012; Valente et al., 2013). However, this variant has also been reported in unaffected family members and does not co-segregate with disease in all families (Captur et al., 2014; Christiaans et al., 2010; Yiu et al., 2012; Morita et al., 2008). Lopes et al. (2013) identified this variant in one patient who also harbored another missense pathogenic variant in the MYBPC3 gene and two missense pathogenic variants in the TTN gene.Collectively, the R495G variant was absent from >2,300 published control alleles (Morita et al., 2008; Frisso et al., 2009; Christiaans et al., 2010; Page et al., 2012). Additionally, the R495G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R495G variant results in a non-conservative amino acid substitution of a positively charged arginine with a non-polar glycine at a residue that is conserved across species (Morita et al., 2008). Other missense variants at the same residue (R495Q, R495W) and variants in nearby residues (V491M, R502Q, R502W) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014).
Invitae RCV000466543 SCV000546465 pathogenic Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 495 of the MYBPC3 protein (p.Arg495Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 22574137). ClinVar contains an entry for this variant (Variation ID: 42537). 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. Different missense substitution at this codon (p.Arg495Trp and p.Arg495Gln) are reported to be deleterious (PMID: 9562578, 23396983, 26671970 for p.Arg495Trp and PMID: 19150014, 20433692, 22765922 for p.Arg495Gln). This indicates that the arginine residue is important for MYBPC3 protein function. In summary, this variant is not present in population databases, has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy, and affects a residue important for protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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