ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1591G>A (p.Gly531Arg) (rs397515912)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2017-05-25 criteria provided, single submitter clinical testing The G531R (c.1591 G>A) variant has been reported in several individuals in association with cardiomyopathy (Olivotto et al., 2008; Waldmüller et al., 2011). In addition, the G531R variant has been published as a different nucleotide change (c.1591 G>C), or unspecified nucleotide change, in multiple other individuals with HCM (Girolami et al., 2006; García-Castro et al., 2009; Millat et al., 2010; Coto et al., 2012; Rubattu et al., 2016). However, some of these individuals harbored a second cardiogenetic variant, and no informative segregation data were reported. The G531R (c.1591 G>A) variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, the G31R 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, this variant lacks significant segregation data and functional evidence, which would further clarify pathogenicity. Based on currently available evidence, G531R is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Ambry Genetics RCV000249319 SCV000317768 uncertain significance Cardiovascular phenotype 2018-01-03 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 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 531 of the MYBPC3 protein (p.Gly531Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs397515912, ExAC 0.003%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 27532257, 21750094, 27600940, 28356264, 27483260, 23508784, 20624503) including one individual who has another pathogenic variant in MYBPC3 (PMID: 20624503). ClinVar contains an entry for this variant (Variation ID: 164109). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 uncertain significance Cardiomyopathy 2018-08-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170958 SCV001351745 likely pathogenic Cardiomyopathy 2020-10-30 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 suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that a different nucleotide change with the same protein effect (c.1591G>C; p.Gly531Arg) was associated with hypercontractile phenotype in the heart tissue engineered from mouse cardiac cells (PMID: 27108529). Considering both c.1591G>A and c.1591G>C nucleotide changes, this variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 19150014, 20624503, 21750094, 21835320, 22765922, 23508784, 27483260, 27532257, 28356264, 32369506). Two of these individuals 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.

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