Submissions for variant NM_000256.3(MYBPC3):c.787G>A (p.Gly263Arg)

gnomAD frequency: 0.00004  dbSNP: rs373730381

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412865	SCV000490635	uncertain significance	not provided	2016-05-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The Gly263Arg variant has been reported as a de novo variant in one patient with HCM and was absent from 120 control individuals; however, functional studies and detailed clinical information were not provided. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project10, indicating it is not a common benign variant in these populations. The Gly263Arg variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528899	SCV000623621	uncertain significance	Hypertrophic cardiomyopathy	2022-10-13	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 263 of the MYBPC3 protein (p.Gly263Arg). This variant is present in population databases (rs373730381, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 15563892, 30847666). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161315). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000617282	SCV000740241	uncertain significance	Cardiovascular phenotype	2023-03-30	criteria provided, single submitter	clinical testing	The p.G263R variant (also known as c.787G>A), located in coding exon 7 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 787. The glycine at codon 263 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported as de novo in an individual with hypertrophic cardiomyopathy (Song L et al. Clin. Chim. Acta, 2005 Jan;351:209-16), as well in in other cardiomyopathy cohorts (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Magrì D et al. J Clin Med, 2020 May;9; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). However, clinical details were limited. This alteration has also been reported in exome cohorts (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). In addition, this alteration has been reported in ostensibly healthy individuals (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770378	SCV000901819	uncertain significance	Cardiomyopathy	2023-05-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000988551	SCV001138315	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001103316	SCV001260057	uncertain significance	Left ventricular noncompaction 10	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000988551	SCV001260058	uncertain significance	Hypertrophic cardiomyopathy 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV000770378	SCV001357612	uncertain significance	Cardiomyopathy	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 263 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: 15563892, 32841044, 33495597, 33782553), and in one instance has been reported to occur de novo (PMID: 15563892). It has also been reported in anindividual affected with sudden death (PMID: 27707468). This variant has been identified in 18/214866 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.
Fulgent Genetics, Fulgent Genetics	RCV002498680	SCV002800839	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-25	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002498680	SCV003925124	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-04-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000528899	SCV004834725	uncertain significance	Hypertrophic cardiomyopathy	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 263 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15563892, 32841044, 33495597, 33782553, 37089884, 37466024), and in one instance has been reported to occur de novo (PMID: 15563892). One of these individuals also carried a likely pathogenic variant in the TNNT2 gene (PMID: 37089884). This variant has also been reported in one individual affected with sudden death (PMID: 27707468). This variant has been identified in 18/214866 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.
CSER _CC_NCGL, University of Washington	RCV000148690	SCV000190417	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000412865	SCV001917648	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000412865	SCV001931883	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412865	SCV001959309	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000412865	SCV001973241	uncertain significance	not provided		no assertion criteria provided	clinical testing