Submissions for variant NM_000256.3(MYBPC3):c.1591G>A (p.Gly531Arg)

dbSNP: rs397515912

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628923	SCV000198900	likely pathogenic	Hypertrophic cardiomyopathy	2020-05-30	criteria provided, single submitter	clinical testing	The p.Gly531Arg variant in MYBPC3 has been reported in association with two distinct nucleotide changes: c.1591G>C and c.1591G>A. Considering both nucleotide changes, this variant has been reported in 1 individual with dilated cardiomyopathy (DCM; c.1591G>A; Waldmuller 2011) and in over 10 individuals with hypertrophic cardiomyopathy (HCM; c.1591G>A: Girolami 2006, Olivotto 2008, Garcia-Castro 2009, Michels 2011, Waldmuller 2011, Walsh 2016, LMM data; c.1591G>C: Millat 2010 , Olivotto 2011, Coto 2012, Rubattu 2016, LMM data). Of the individuals with HCM, at least 4 individuals carried a second pathogenic MYBPC3 variant and had early onset disease (LMM data, Millat 2010, Rubattu 2016). Furthermore, the c.1591G>C variant was found by our laboratory to segregate with disease in 2 affected relatives from 1 family. This variant has also been reported by other clinical laboratories in ClinVar (Variation IDs: 164109 (c.1591G>A) and 42550 (c.1591G>C)). Additionally, the c.1591G>A variant has been identified in 0.005% (1/17952) of East Asian and in 0.005% (6/111606) of European chromosomes by gnomAD, while the c.1591G>C variant has been identified in 0.003% (4/127020) of European chromosomes and 0.004% (1/24164) of African chromosomes in gnomAD (https://gnomad.broadinstitute.org/). A functional study in which the c.1591G>C (p.Gly531Arg) variant was transfected into MYBPC3 knockout mouse cardiomyocytes alone and in combination with wild-type MYBPC3 (to represent homozygous and heterozygous disease states) revealed abnormal contractile force in both scenarios compared to wild-type (Wijnker 2016). Computational prediction tools and conservation analysis also suggest that the variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS3_Supporting, PM2, PS4_Moderate, PP3.
GeneDx	RCV000497291	SCV000208035	likely pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Published functional studies of G531R (c.1591G>C) suggest a damaging effect (Wijinker et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16858239, 27532257, 20031602, 19150014, 20173211, 20594303, 21750094, 22765922, 23690394, 23508784, 27590665, 28356264, 28193612, 28152038, 28679633, 33673806, 18533079, 32369506, 27108529, 35130036, Emrahi2022, 36264615)
Ambry Genetics	RCV000249319	SCV000317768	uncertain significance	Cardiovascular phenotype	2022-07-13	criteria provided, single submitter	clinical testing	The p.G531R variant (also known as c.1591G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1591. The glycine at codon 531 is replaced by arginine, an amino acid with dissimilar properties. This variant and another variant leading to the same amino acid substitution (MYBPC3 c.1591G>C) have been reported in multiple unrelated patients with hypertrophic cardiomyopathy, several of whom also carried other, pathogenic MYBPC3 mutations, and in dilated cardiomyopathy and noncompaction cardiomyopathy cohorts (Millat G et al. Eur J Med Genet. 2006;53:261-7; García-Castro M et al. Rev Esp Cardiol. 2009;62:48-56; Di Donna P et al. Europace. 2010;12:347-55; Olivotto I et al. J. Am. Coll. Cardiol. 2011;58:839-48; Waldmüller S et al. Eur. J. Heart Fail. 2011;13:1185-92; Rubattu S et al. Int J Mol Sci. 2016;17(8):1239; Miszalski-Jamka K et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Walsh R et al. Genet. Med. 2017;19:192-203; personal communication from the Laboratory of Molecular Medicine). In a functional study utilizing engineered heart tissue derived from MYBPC3 knockout cardiomyocytes, c.1591G>C p.G531R was unable to completely rescue the hypercontractile phenotype of the knockout tissue; however, the physiological relevance of this result is unclear (Wijnker PJ et al. J. Mol. Cell. Cardiol. 2016;97:82-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000497291	SCV000748017	likely pathogenic	not provided	2016-05-29	criteria provided, single submitter	clinical testing
Invitae	RCV000628923	SCV000749831	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-06	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 531 of the MYBPC3 protein (p.Gly531Arg). This variant is present in population databases (rs397515912, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 21750094, 23508784, 27483260, 27532257, 27600940, 28356264, 33673806). ClinVar contains an entry for this variant (Variation ID: 164109). 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170958	SCV001333614	likely pathogenic	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170958	SCV001351745	likely pathogenic	Cardiomyopathy	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 531 of the MYBPC3 protein (c.1591G>A; p.Gly531Arg). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that a different nucleotide change with the same protein effect (c.1591G>C; p.Gly531Arg; ClinVar variation ID: 164109) does not fully rescue the hypercontractile phenotype of heart tissue from Mybpc3 knockout mouse (PMID: 27108529). Considering both c.1591G>A and c.1591G>C nucleotide changes, the p.Gly531Arg missense variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 19150014, 20624503, 21750094, 21835320, 22765922, 23508784, 27483260, 27532257, 28356264, 32369506, 33495597, 33673806). Two of these individuals also carried a different pathogenic variant in the same gene (PMID: 20624503, 27483260), and one of them showed early-onset of disease before age 25 (PMID: 27483260). This variant has been identified in 8/247086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000497291	SCV002017837	likely pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000497291	SCV002103241	likely pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing	PP3, PM2, PS3_supporting, PS4_moderate
CeGaT Center for Human Genetics Tuebingen	RCV000497291	SCV002497119	likely pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003314567	SCV004014718	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-05-22	criteria provided, single submitter	clinical testing	The MYBPC3 c.1591G>A (p.Gly531Arg) missense variant has been reported in two individuals with hypertrophic cardiomyopathy (HCM) and one with dilated cardiomyopathy (PMID: 21750094; 33673806). A c.1591G>C variant, which results in the same amino acid change, has been reported in at least five unrelated individuals with HCM and has been shown to segregate with the disease in the affected child of one proband (PMID: 21835320; 24793961; 25351510; 27532257; doi:10.1016/j.genrep.2021.101471). The c.1591G>C variant has also been reported in two individuals with early-onset disease who carried a second variant in MYBPC3 (PMID: 27483260). In addition, the p.Gly531Arg variant has been identified in at least three additional individuals with HCM without the nucleotide change being specified (PMID: 16858239; 20031602; 22765922). The c.1591G>A variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Functional studies demonstrated that the c.1591G>A (p.Gly531Arg) variant was unable to restore maximal force to the wild-type level when it was co-expressed with the wild-type protein in engineered heart tissue from MYBPC3 knock-out mice (PMID: 27108529). Based on the available evidence, the c.1591G>A (p.Gly531Arg) variant is classified as likely pathogenic for hypertrophic cardiomyopathy.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000497291	SCV001959075	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000497291	SCV001964808	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000497291	SCV002035794	likely pathogenic	not provided		no assertion criteria provided	clinical testing