Submissions for variant NM_000256.3(MYBPC3):c.133G>A (p.Gly45Arg)

gnomAD frequency: 0.00002  dbSNP: rs775837337

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001180183	SCV001345051	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 45 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27841901, 32841044). It has also been reported in an individual affected with long QT syndrome (PMID: 31376648). This variant has been identified in 5/240712 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.
Ambry Genetics	RCV002379698	SCV002694534	uncertain significance	Cardiovascular phenotype	2022-06-22	criteria provided, single submitter	clinical testing	The p.G45R variant (also known as c.133G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 133. The glycine at codon 45 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Ntusi NA et al. Cardiovasc J Afr;27:152-158; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405). This amino acid position is poorly 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.
Fulgent Genetics, Fulgent Genetics	RCV002483981	SCV002790632	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002558942	SCV003461587	uncertain significance	Hypertrophic cardiomyopathy	2024-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 45 of the MYBPC3 protein (p.Gly45Arg). 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: 27841901, 33782553). ClinVar contains an entry for this variant (Variation ID: 921040). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
All of Us Research Program, National Institutes of Health	RCV002558942	SCV004844985	uncertain significance	Hypertrophic cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 45 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27841901, 32841044). It has also been reported in an individual affected with long QT syndrome (PMID: 31376648). This variant has been identified in 5/240712 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.
GeneDx	RCV001702585	SCV005421345	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Identified in patients with HCM, DCM, and LQTS; at least one patient harbored additional cardiogenetic variants (PMID: 29875424, 31983221, 27841901, 31376648, 32841044); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33782553, 31376648, 27841901, 32841044, 29875424, 31983221)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702585	SCV001932100	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702585	SCV001968480	uncertain significance	not provided		no assertion criteria provided	clinical testing