Submissions for variant NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)

dbSNP: rs397515905

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000543508	SCV000198913	likely pathogenic	Hypertrophic cardiomyopathy	2023-04-06	criteria provided, single submitter	clinical testing	The p.Arg495Trp variant in MYBPC3 has been reported in at least 15 individuals with hypertrophic cardiomyopathy (HCM; Rodríguez-García 2010 PMID: 20433692, Coto 2012 PMID: 22765922, Rubattu 2016 PMID: 27483260, Walsh 2017 PMID: 27532257, Restrepo-Cordoba 2017 PMID: 28138913, Kim 2020 PMID: 32492895, Lipari 2020 PMID: 31919335, Sepp 2022 PMID: 35626289, LMM data), including in 1 individual who also had another pathogenic variant in MYBPC3 (Berge 2014 PMID: 24111713). This variant was also been identified by other clinical laboratories in ClinVar (Variation ID: 164114) and has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additionally, a variant involving this codon (p.Arg495Gln) have been identified in individuals with HCM and has been classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5.
Invitae	RCV000543508	SCV000623527	pathogenic	Hypertrophic cardiomyopathy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 495 of the MYBPC3 protein (p.Arg495Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 27532257). ClinVar contains an entry for this variant (Variation ID: 164114). 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: 11499718, 18403758, 19659763, 20019025, 20624503, 22857948, 23396983, 24093860, 27532257). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770365	SCV000901806	pathogenic	Cardiomyopathy	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193929	SCV001363106	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2019-05-13	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1483C>T (p.Arg495Trp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) domain and Immunoglobulin I-set (IPR013098) domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249906 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Garcia-Castro_2009, Coto_2012, Rodriguez-Garcia_2010, Walsh_2017). These data indicate that the variant may be associated with disease. However, this variant was also found in two asymptomatic family members (Garcia-Castro_2009), suggesting incomplete penetrance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense change at this codon has been classified as pathogenic by our laboratory (p.Arg495Gly). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265564	SCV001443721	pathogenic	Hypertrophic cardiomyopathy 4	2019-10-22	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 19150014, 22765922, 27532257). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1483C>T (p.Arg495Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1483C>T (p.Arg495Trp) variant is classified as Pathogenic.
Ambry Genetics	RCV002390322	SCV002698879	likely pathogenic	Cardiovascular phenotype	2024-03-12	criteria provided, single submitter	clinical testing	The p.R495W variant (also known as c.1483C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1483. The arginine at codon 495 is replaced by tryptophan, an amino acid with dissimilar properties. In one family, this variant was detected in a proband and maternal grandfather both reported to have hypertrophy, and was also detected in the proband's unaffected mother (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56). This variant has also been detected in other probands reported to have hypertrophic cardiomyopathy (HCM) and in HCM cohorts where, in some cases, clinical detail was limited or another variant was also detected (Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart. 2015 Feb;101(4):294-301; Rubattu S et al. Int J Mol Sci, 2016 Jul;17(8); Walsh R et al. Genet. Med., 2017 02;19:192-203;Lipari M et al. Pol Arch Intern Med, 2020 02;130:89-99). This alteration was also reported in one individual from a dilated cardiomyopathy (DCM) cohort (Mazzarotto F et al. Circulation, 2020 02;141:387-398). Another alteration at the same codon, p.R495Q (c.1484G>A), has been reported in association with HCM (Niimura H et al. N. Engl. J. Med. 1998 Apr;338(18):1248-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Illumina Laboratory Services, Illumina	RCV001265564	SCV004014743	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-05-19	criteria provided, single submitter	clinical testing	The MYBPC3 c.1483C>T (p.Arg495Trp) missense variant has been identified in a heterozygous state in at least five individuals with hypertrophic cardiomyopathy (PMID: 19150014; PMID: 22765922; PMID: 27532257). The variant has also been found in a heterozygous state in asymptomatic individuals suggesting reduced penetrance (PMID: 19150014). The c.1483C>T variant was not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, two different amino acid substitutions at the same codon [(p.Arg495Gln) and (p.Arg495Gly)] have been reported in individuals with hypertrophic cardiomyopathy (PMID: 27532257; ClinVar). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic or likely pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1483C>T (p.Arg495Trp) variant is classified as likely pathogenic for hypertrophic cardiomyopathy.
Neuberg Centre For Genomic Medicine, NCGM	RCV001265564	SCV004175775	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-03-01	criteria provided, single submitter	clinical testing	The missense variant c.1483C>T(p.Arg495Trp) in MYBPC3 gene has been observed in heterozygous state in multiple individuals with hypertrophic cardiomyopathy (Coto et. al., 2012; García-Castro et. al., 2009). The p.Arg495Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic / Likely_pathogenic (multiple submitters). The amino acid change p.Arg495Trp in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant disrupts the p.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Marsiglia JD et. al., 2013). The amino acid Arg at position 495 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000770365	SCV004358724	likely pathogenic	Cardiomyopathy	2022-01-05	criteria provided, single submitter	clinical testing	This missense variant is located 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 at least 10 unrelated individuals affected with hypertrophic cardiomyopathy and in a few asymptomatic relatives (PMID: 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg495Gln and p.Arg495Gly, are known to be pathogenic (ClinVar variation ID: 164113, 42537), indicating that arginine at this position is important for the MYBPC3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000543508	SCV004834617	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant is located 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 at least 10 unrelated individuals affected with hypertrophic cardiomyopathy and in a few asymptomatic relatives (PMID: 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg495Gln and p.Arg495Gly, are known to be pathogenic (ClinVar variation ID: 164113, 42537), indicating that arginine at this position is important for the MYBPC3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000543508	SCV001430846	likely pathogenic	Hypertrophic cardiomyopathy	2019-12-06	no assertion criteria provided	research	The MYBPC3 Arg495Trp variant has been reported in at least >10 HCM cases (see literature), and was found to segregate in one family (García-Castro M, et al., 2009). We have identified this variant in a HCM proband of East Asian descent, with no family history of disease. The variant is present at a low frequency in the Genome Aggregation Database (AF=0.000007; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Furthermore different rare variants at this position (Arg495Gln and Arg495Gly) have been reported as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) the variant has been reported in more than 10 HCM probands (PS4_supporting), is rare in the general population (PM2), other amino acid changes at this position have been classified as pathogenic (PM5) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYBPC3 Arg495Trp as 'likely pathogenic'.
Clinical Genetics, Academic Medical Center	RCV001698977	SCV001925939	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001698977	SCV001956195	pathogenic	not provided		no assertion criteria provided	clinical testing