Submissions for variant NM_000256.3(MYBPC3):c.2909G>A (p.Arg970Gln)

gnomAD frequency: 0.00003  dbSNP: rs727504346

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154467	SCV000204136	uncertain significance	not specified	2019-08-02	criteria provided, single submitter	clinical testing	The p.Arg970Gln variant in MYBPC3 has been identified in 1 individual with DCM, 2 individuals with HCM, and 1 individual with LVNC (Walsh 2017, Ko 2018, Takasaki 2018, LMM data). It has also been identified in 0.02% (6/28490) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177832). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None.
Eurofins Ntd Llc (ga)	RCV000724501	SCV000228595	uncertain significance	not provided	2015-02-19	criteria provided, single submitter	clinical testing
Invitae	RCV000462920	SCV000546442	uncertain significance	Hypertrophic cardiomyopathy	2024-01-04	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 970 of the MYBPC3 protein (p.Arg970Gln). This variant is present in population databases (rs727504346, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 22464770, 27532257, 28640247, 30188508, 30297972). ClinVar contains an entry for this variant (Variation ID: 177832). 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. 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	RCV000617862	SCV000737381	uncertain significance	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The p.R970Q variant (also known as c.2909G>A), located in coding exon 28 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2909. The arginine at codon 970 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC), but clinical details were limited (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Ko C et al. Genet Med, 2018 01;20:69-75). This variant was also detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000777993	SCV000914099	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 970 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 at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in an individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154467	SCV001448478	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2909G>A (p.Arg970Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 184920 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (5.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2909G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Lakdawala_2012, Pugh_2014, Walsh_2017, Ko_2018, Ho_2018, Takasaki_2018). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000724501	SCV001788958	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	Identified in several individuals with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Lakdawala et al., 2012; Pugh et al., 2014; Walsh et al., 2017; Ko et al., 2018; Takasaki et al., 2018; van Lint et al., 2019; Hirono et al., 2020; Stava et al., 2022); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24503780, 22464770, 28640247, 30188508, 32600061, 33782553, 35653365, 30847666, 30297972, 27532257, 34819141)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777993	SCV003838937	uncertain significance	Cardiomyopathy	2021-07-20	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000724501	SCV000925164	uncertain significance	not provided	2018-02-02	no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000724501	SCV001925531	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724501	SCV001955287	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724501	SCV001975841	uncertain significance	not provided		no assertion criteria provided	clinical testing