ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505710 SCV000208365 likely pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing The G531R (c.1591 G>C) variant has been reported in several individuals in association with cardiomyopathy (Millat et al., 2010; Olivotto et al., 2011; Lopes et al., 2015; Rubattu et al., 2016; Walsh et al., 2017). In addition, the G531R variant has been published as a different nucleotide change (c.1591 G>A), or unspecified nucleotide change, in multiple other individuals with HCM (Girolami et al., 2006; Olivotto et al., 2008; García-Castro et al., 2009; Waldmüller et al., 2011; Coto et al., 2012; Valente et al., 2013; Walsh et al., 2017). However, some of these individuals harbored a second cardiogenetic variant, and no informative segregation data were reported. The G531R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G531R 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. 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. Finally, a functional study examining the effects of the G531R variant in mouse-derived engineered heart tissue demonstrated that tissue expressing the G531R variant is associated with a hypercontractile phenotype compared to wild type cardiac tissue (Wijnker et al., 2016).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035416 SCV000059064 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 distinct nucleotide changes: c.1591G>C and c.1591G>A. Considering both nucleotide changes, this var iant has been reported in 1 individual with DCM (c.1591G>A; Waldmuller 2011) and >10 individuals with HCM, including at least 4 individuals who carried a second pathogenic MYBPC3 variant (c.1591G>A: Girolami 2006, Olivotto 2008, Garcia-Cast ro 2009, Michels 2011, Waldmuller 2011, Walsh 2016, LMM ; c.1591G>C: Millat 2010 , Olivotto 2011, Coto 2012, Rubattu 2016, LMM data). Furthermore, the c.1591G>C variant was found by our laboratory to segregate with disease in 2 affected rela tives from 1 family. This variant has also been identified in 5/125272 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs397515912). In vitro functional studies provide some evidence that the p.Gly531Arg variant may impact protein function (Wijnker 2016). Howeve r, these types of assays may not accurately represent biological function. Compu tational prediction tools and conservation analysis also suggest that the varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, while there is some suspicion for a pathogeni c role, the clinical significance of the p.Gly531Arg variant is uncertain.

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