Submissions for variant NM_000256.3(MYBPC3):c.842G>A (p.Arg281Gln)

gnomAD frequency: 0.00004  dbSNP: rs11570060

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628952	SCV000749860	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 281 of the MYBPC3 protein (p.Arg281Gln). 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: 20800588, 30685992). ClinVar contains an entry for this variant (Variation ID: 525001). 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 tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV000764976	SCV000896153	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179126	SCV001343733	uncertain significance	Cardiomyopathy	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 281 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 20800588, 30685992). This variant has been identified in 11/217880 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.
Genetics and Genomics Program, Sidra Medicine	RCV000628952	SCV001434092	likely benign	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001700428	SCV002497121	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413789	SCV002675884	uncertain significance	Cardiovascular phenotype	2023-02-13	criteria provided, single submitter	clinical testing	The p.R281Q variant (also known as c.842G>A), located in coding exon 8 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 842. The arginine at codon 281 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified in hypertrophic cardiomyopathy cohorts; however, details were not provided (Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91; Nagyova E et al. Bratisl Lek Listy, 2019;120:46-51). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001700428	SCV001925958	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700428	SCV001954575	uncertain significance	not provided		no assertion criteria provided	clinical testing