ClinVar Miner

Submissions for variant NM_001613.4(ACTA2):c.115C>T (p.Arg39Cys) (rs112901682)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000143866 SCV000188734 pathogenic Thoracic aortic aneurysm and aortic dissection 2014-01-30 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000143866 SCV000902099 likely pathogenic Thoracic aortic aneurysm and aortic dissection 2016-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000490091 SCV000576794 likely pathogenic not provided 2017-04-19 criteria provided, single submitter clinical testing The R39C variant has been published several times in association with TAAD (Regalado et al., 2014; Regalado et al., 2015; Guo et al., 2009; Iman et al., 2011; Campens et al., 2015) or a family history of TAAD (Renard et al., 2013; Hoffjan et al., 2011). The R39C 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 R39C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant at the same residue (R39H) and in nearby residues (G38R H42N, V45L, M49V) have been reported in the Human Gene Mutation Database in association with TAAD (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of the R39C variant, although the evidence suggests this variant is likely disease-causing.
Invitae RCV000055647 SCV000646310 pathogenic Aortic aneurysm, familial thoracic 6 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 39 of the ACTA2 protein (p.Arg39Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with aortopathy and has been shown to segregate with the disease in one family (PMID: 21248741,21733706, 21937134, 24243736, 25644172, 25759435). ClinVar contains an entry for this variant (Variation ID: 65449). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000055647 SCV000083872 pathogenic Aortic aneurysm, familial thoracic 6 2011-05-01 no assertion criteria provided literature only

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