Submissions for variant NM_000256.3(MYBPC3):c.817C>T (p.Arg273Cys)

gnomAD frequency: 0.00001  dbSNP: rs551119259

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526965	SCV000623624	uncertain significance	Hypertrophic cardiomyopathy	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 273 of the MYBPC3 protein (p.Arg273Cys). 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 missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21425739, 28356264). ClinVar contains an entry for this variant (Variation ID: 454334). 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.
Mendelics	RCV000988550	SCV001138314	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190480	SCV001357980	uncertain significance	Cardiomyopathy	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 273 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 21425739, 28356264) and in an individual affected with sudden cardiac death (PMID: 26688388). It has also been reported in an individual affected with long QT syndrome (PMID: 34395343); this individual also carried variant in the KCNQ1 gene. This variant has been identified in 2/175154 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000988550	SCV001369730	uncertain significance	Hypertrophic cardiomyopathy 4	2020-03-13	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3,BS2.
Ambry Genetics	RCV002431510	SCV002681288	uncertain significance	Cardiovascular phenotype	2024-06-10	criteria provided, single submitter	clinical testing	The p.R273C variant (also known as c.817C>T), located in coding exon 7 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 817. The arginine at codon 273 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported alone and with alterations in other cardiac-related genes in subjects with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and prolonged QT (Santos S et al. Rev Port Cardiol, 2011 Jan;30:7-18; Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5; Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Girolami F et al. J Am Coll Cardiol, 2010 Apr;55:1444-53; Chida A et al. Heart Vessels, 2017 Jun;32:700-707; Sarquella-Brugada G et al. Front Pediatr, 2021 Jul;9:704580). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000526965	SCV004834720	uncertain significance	Hypertrophic cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 273 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 21425739, 28356264) and in an individual affected with sudden cardiac death (PMID: 26688388). This variant has been identified in 2/175154 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.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV004767331	SCV005380293	uncertain significance	not provided		criteria provided, single submitter	not provided