Submissions for variant NM_000256.3(MYBPC3):c.2450G>A (p.Arg817Gln)

gnomAD frequency: 0.00001  dbSNP: rs397515964

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035489	SCV000059139	uncertain significance	not specified	2011-02-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Arg817Gln v ariant has not been reported in the literature. This variant has been identified by our laboratory in 2 other HCM probands (1 Asian, 1 Black). The variant was not detected in 414 White and 368 Black control chromosomes, suggesting this var iant is not common in these populations. Furthermore, arginine (Arg) at position 817 is highly conserved across several species, indicating the change observed in this individual may negatively affect the MYBPC3 protein function. In summary , absence from healthy controls and evolutionary conservation of the amino acid are consistent with a pathogenic role; however, additional studies are needed to determine its significance with certainty.
GeneDx	RCV000766352	SCV000208093	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple unrelated individuals with hypertrophic cardiomyopathy in the published literature, but familial segregation information and additional clinical information were not included (Murphy et al., 2016; Walsh et al., 2017; Viswanathan et al., 2017; Thompson et al., 2021); This variant is associated with the following publications: (PMID: 27532257, 29121657, 33782553, 26914223)
Invitae	RCV000459809	SCV000546496	pathogenic	Hypertrophic cardiomyopathy	2023-12-04	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 817 of the MYBPC3 protein (p.Arg817Gln). This variant is present in population databases (rs397515964, gnomAD 0.008%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42621). 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 disruptive. This variant disrupts the p.Arg817 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25351510, 26914223, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170417	SCV001332995	uncertain significance	Cardiomyopathy	2019-03-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372599	SCV004080191	uncertain significance	Cardiovascular phenotype	2023-09-19	criteria provided, single submitter	clinical testing	The p.R817Q variant (also known as c.2450G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2450. The arginine at codon 817 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). This amino acid position is highly 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.