ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2500C>T (p.Arg834Trp)

gnomAD frequency: 0.00002  dbSNP: rs752007810
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000554970 SCV000623559 uncertain significance Hypertrophic cardiomyopathy 2024-11-03 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 834 of the MYBPC3 protein (p.Arg834Trp). This variant is present in population databases (rs752007810, gnomAD 0.003%). This missense change has been observed in individual(s) with sudden cardiac death and/or hypertrophic cardiomyopathy (PMID: 14563344, 34667957). ClinVar contains an entry for this variant (Variation ID: 454314). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000625023 SCV000743552 uncertain significance Hypertrophic cardiomyopathy 4 2016-12-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000625023 SCV000744839 uncertain significance Hypertrophic cardiomyopathy 4 2017-05-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001177627 SCV001341868 uncertain significance Cardiomyopathy 2023-03-28 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 834 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset hypertrophic cardiomyopathy and sudden cardiac death, who also carried a pathogenic variant in the same gene (PMID: 14563344, 17908752), and in an individual who suffered sudden death (PMID: 27114410, 34667957, 34949102). This variant has been identified in 3/249090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002431509 SCV002742769 uncertain significance Cardiovascular phenotype 2021-05-28 criteria provided, single submitter clinical testing The p.R834W variant (also known as c.2500C>T), located in coding exon 25 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2500. The arginine at codon 834 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a sudden cardiac death subject, who also carried another missense alteration in MYBPC3 (Alders M et al. Eur Heart J, 2003 Oct;24:1848-53; Hofman N et al. Pediatrics, 2007 Oct;120:e967-73). This variant was also reported in another case of sudden cardiac death in a subject with a personal and family history of syncope (Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV000554970 SCV004839248 uncertain significance Hypertrophic cardiomyopathy 2024-08-06 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 834 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset hypertrophic cardiomyopathy and sudden cardiac death, who also carried a pathogenic variant in the same gene (PMID: 14563344, 17908752), and in an individual who suffered sudden death (PMID: 27114410, 34667957, 34949102). This variant has been identified in 3/249090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000994630 SCV001953136 uncertain significance not provided no assertion criteria provided clinical testing

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