ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151124 SCV000198900 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly531Arg variant in MYBPC3 has been reported in association with two nucleotide changes: c.1591G>C and c.1591G>A. Considering both nucleotide changes, this variant has been reported in 1 individual with DCM (c.1591G>A; Waldmuller 2011) and >10 indi viduals with HCM, including at least 4 individuals who carried a second pathogen ic MYBPC3 variant (c.1591G>A: Girolami 2006, Olivotto 2008, Garcia-Castro 2009, Michels 2011, Waldmuller 2011, Walsh 2016, LMM ; c.1591G>C: Millat 2010, Olivott o 2011, Coto 2012, Rubattu 2016, LMM data). The c.1591G>C variant was found by o ur laboratory to segregate with disease in 2 affected relatives from 1 family. T his variant has also been identified in 5/110302 European chromosomes by the Gen ome Aggregation Database (gnomAD,; dbSNP rs397 515912). In vitro functional studies provide some evidence that the p.Gly531Arg variant may impact protein function (Wijnker 2016). However, these types of assa ys may not accurately represent biological function. Computational prediction to ols and conservation analysis also suggest that the variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical s ignificance of the p.Gly531Arg variant is uncertain.
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 Lines of evidence used in support of classification: Insufficient evidence
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 2018-11-26 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.

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