Submissions for variant NM_000256.3(MYBPC3):c.2683C>T (p.Arg895Cys)

gnomAD frequency: 0.00003  dbSNP: rs374976635

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000473577	SCV000546452	uncertain significance	Hypertrophic cardiomyopathy	2023-12-19	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 895 of the MYBPC3 protein (p.Arg895Cys). 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 individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 407320). 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.
Center for Human Genetics, University of Leuven	RCV000473577	SCV000886823	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177377	SCV001341575	uncertain significance	Cardiomyopathy	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 895 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 hypertrophic cardiomyopathy (PMID: 31513939). This variant has not been identified 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.
GeneDx	RCV001753880	SCV001995056	uncertain significance	not provided	2019-10-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by two other laboratories (ClinVar Variant ID#407320; Landrum 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: 31513939)
Fulgent Genetics, Fulgent Genetics	RCV002481420	SCV002794064	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-07-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003168777	SCV003911867	uncertain significance	Cardiovascular phenotype	2022-11-04	criteria provided, single submitter	clinical testing	The p.R895C variant (also known as c.2683C>T), located in coding exon 26 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2683. The arginine at codon 895 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort (Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.