ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2458C>T (p.Arg820Trp)

dbSNP: rs775404728
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458652 SCV000546424 pathogenic Hypertrophic cardiomyopathy 2023-06-04 criteria provided, single submitter clinical testing This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 20542340, 28771489, 33782553; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 820 of the MYBPC3 protein (p.Arg820Trp). ClinVar contains an entry for this variant (Variation ID: 195850). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg820 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12628722, 22112859, 22267749, 25281569). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 17521870, 24906243, 26776584). 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000604898 SCV000743553 pathogenic Hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
GeneDx RCV000176522 SCV001765382 likely pathogenic not provided 2019-12-04 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 195850; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30284024, 19566849, 26776581, 28868097, 21147473, 26776585, 25622655, 26776584, 27076529, 26776595, 24602043, 21051304, 24906243, 23323744, 17521870, 21415409, 24447051, 29907873, 19035361, 29636697, 28642712, 28679633, 28771489, 20542340)
Ambry Genetics RCV002453626 SCV002738183 likely pathogenic Cardiovascular phenotype 2023-11-21 criteria provided, single submitter clinical testing The p.R820W variant (also known as c.2458C>T), located in coding exon 25 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2458. The arginine at codon 820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the heterozygous and homozygous states in individuals with hypertrophic cardiomyopathy (HCM); however, heterozygous relatives of the homozygous proband were reportedly unaffected (Ripoll Vera T et al, Int. J. Cardiol. 2010 Nov; 145(2):405-7; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Chung H et al. Cardiovasc Ultrasound, 2021 Jan;19:4; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799; Ambry internal data). The same alteration (p.R820W) has also been detected in ragdoll cats exhibiting HCM (Meurs KM et al. Genomics, 2007 Aug;90:261-4). Another alteration at the same codon, p.R820Q (c.2459G>A), has been detected in individuals with HCM (Konno T et al. J. Am. Coll. Cardiol., 2003 Mar;41:781-6). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003150049 SCV003838941 likely pathogenic Cardiomyopathy 2021-09-03 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000604898 SCV004810193 pathogenic Hypertrophic cardiomyopathy 4 2024-04-04 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000176522 SCV000228192 uncertain significance not provided 2015-05-04 flagged submission clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000604898 SCV000733040 likely pathogenic Hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000176522 SCV001713562 uncertain significance not provided 2019-06-17 flagged submission clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000176522 SCV001957711 likely pathogenic not provided no assertion criteria provided clinical testing

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