Submissions for variant NM_000256.3(MYBPC3):c.1765C>T (p.Arg589Cys)

gnomAD frequency: 0.00001  dbSNP: rs1329919535

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617974	SCV000740170	uncertain significance	Cardiovascular phenotype	2017-05-30	criteria provided, single submitter	clinical testing	The p.R589C variant (also known as c.1765C>T), located in coding exon 18 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1765. The arginine at codon 589 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in two hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart. 2015;101:294-301; Ingles J et al. Circ Cardiovasc Genet. 2017;10(2):e001620). Based on data from gnomAD, the T allele was reported in 2 of 197602 (0.001%) total alleles. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817221	SCV000957771	uncertain significance	Hypertrophic cardiomyopathy	2024-09-08	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 589 of the MYBPC3 protein (p.Arg589Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28408708, 28790153, 37652022). ClinVar contains an entry for this variant (Variation ID: 520358). 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.Arg589 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 27476098, 30105547), which suggests that this may be a clinically significant amino acid residue. 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.
GeneDx	RCV001561795	SCV001784457	uncertain significance	not provided	2021-01-14	criteria provided, single submitter	clinical testing	Identified in patients with HCM in the published literature; however, at least one individual harbored an additional cardiogenetic variant (Lopes et al., 2015; Burns et al., 2017); 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; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 520358; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28790153, 25351510)
All of Us Research Program, National Institutes of Health	RCV000817221	SCV004842450	uncertain significance	Hypertrophic cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 589 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 2 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 28408708). This variant has been identified in 2/200544 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.