ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2497G>A (p.Ala833Thr) (rs200854335)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621540 SCV000739957 uncertain significance Cardiovascular phenotype 2016-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171868 SCV000054731 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000143867 SCV000188735 uncertain significance Cardiomyopathy 2015-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000413572 SCV000492082 uncertain significance not specified 2016-11-28 criteria provided, single submitter clinical testing The A833T variant in the ACTN2 gene has been reported as a variant of uncertain significance in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). This variant has also been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000188735.2 ; Landrum et al., 2016). Nevertheless, the A833T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A833T 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. Finally, in silico analysis suggests that this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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