Submissions for variant NM_000256.3(MYBPC3):c.2915G>A (p.Arg972Gln)

gnomAD frequency: 0.00001  dbSNP: rs761696555

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187354	SCV001354128	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 972 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: 32841044). This variant has been identified in 9/185428 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.
Invitae	RCV001876194	SCV002204646	uncertain significance	Hypertrophic cardiomyopathy	2024-01-20	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 972 of the MYBPC3 protein (p.Arg972Gln). This variant is present in population databases (rs761696555, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29875424, 32815737, 33782553). ClinVar contains an entry for this variant (Variation ID: 925428). 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.
Ambry Genetics	RCV002436757	SCV002748705	uncertain significance	Cardiovascular phenotype	2020-07-09	criteria provided, single submitter	clinical testing	The p.R972Q variant (also known as c.2915G>A), located in coding exon 28 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2915. The arginine at codon 972 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in 1 individual from a hypertrophic cardiomyopathy (HCM) cohort as well as in a population-based cohort (Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224524	SCV003920223	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-03-30	criteria provided, single submitter	clinical testing	MYBPC3 NM_000256.3 exon 27 p.Arg972Gln (c.2915G>A): This variant has not been reported in the literature but is present in 3/26910 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs761696555). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226439	SCV003922589	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2915G>A (p.Arg972Gln) results in a conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 185428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2915G>A has been reported in the literature in individuals affected with Cardiomyopathy (Mazzarotto_2019, Pua_2020, Thompson_2021, Kurzlechner_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with pathogenic variants have been reported (MYH7 c.2710C>T, p.Arg904Cys; MYBPC3 c.1504C>T, p.Arg502Trp) (Kurzlechner_2022 and Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.