Submissions for variant NM_000256.3(MYBPC3):c.1409G>A (p.Arg470Gln)

gnomAD frequency: 0.00001  dbSNP: rs776734314

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455266	SCV000539823	uncertain significance	not specified	2016-03-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 1/11104 Latino;
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770371	SCV000901812	uncertain significance	Cardiomyopathy	2015-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770371	SCV001359451	uncertain significance	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 470 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: 27483260, 27600940, 29398688, 33495597) and in an individual affected with aortic dissection (PMID: 30959811). This variant has been identified in 1/247146 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	RCV001224403	SCV001396595	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-25	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 470 of the MYBPC3 protein (p.Arg470Gln). This variant is present in population databases (rs776734314, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27483260, 27600940, 29398688; Invitae). ClinVar contains an entry for this variant (Variation ID: 403203). 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.Arg470 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23233322, 33782553). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001591057	SCV001815033	uncertain significance	not provided	2019-01-18	criteria provided, single submitter	clinical testing	Reported in association with HCM (Rubattu et al., 2016; Cecconi et al., 2016; Teramoto et al., 2018); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 403203; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27483260, 25320358, 28679633, 27600940, 21415409, 29398688)
Ambry Genetics	RCV002393070	SCV002698939	uncertain significance	Cardiovascular phenotype	2022-03-07	criteria provided, single submitter	clinical testing	The p.R470Q variant (also known as c.1409G>A), located in coding exon 16 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1409. The arginine at codon 470 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts, as well as a sudden unexplained death cohort (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Teramoto R et al. Circ J, 2018 03;82:1139-1148; Hata Y et al. J Clin Med, 2019 Apr;8:[ePub ahead of print]). 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.