ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.895C>T (p.Arg299Cys) (rs779109533)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766962 SCV000619571 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The R299C variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory (ClinVar SCV000271499.1; Landrum et al., 2016). The R299C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, R299C 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. Furthermore, 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. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000217578 SCV000271499 uncertain significance not specified 2015-03-11 criteria provided, single submitter clinical testing The p.Arg299Cys variant in ACTN2 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the Arg299Cys variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, the clinical significance of the Arg299Cys varia nt is uncertain.

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