Submissions for variant NM_000256.3(MYBPC3):c.2927C>G (p.Pro976Arg)

gnomAD frequency: 0.00001  dbSNP: rs954096716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002438611	SCV002748754	uncertain significance	Cardiovascular phenotype	2022-06-16	criteria provided, single submitter	clinical testing	The p.P976R variant (also known as c.2927C>G), located in coding exon 28 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 2927. The proline at codon 976 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in one subject with hypertrophic cardiomyopathy (HCM) (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). This variant was also detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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.
Fulgent Genetics, Fulgent Genetics	RCV002498993	SCV002813380	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531732	SCV003276625	uncertain significance	Hypertrophic cardiomyopathy	2022-10-14	criteria provided, single submitter	clinical testing	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. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 976 of the MYBPC3 protein (p.Pro976Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 21750094, 30847666). ClinVar contains an entry for this variant (Variation ID: 518241). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000600797	SCV000733031	uncertain significance	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700238	SCV001921575	uncertain significance	not provided		no assertion criteria provided	clinical testing