ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs112901682
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490091 SCV000576794 pathogenic not provided 2023-05-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21733706, 25644172, 25759435, 24243736, 21248741, 21937134, 30030203, 29907982, 31536524, 35567597, 36053285, 34498425)
Invitae RCV000055647 SCV000646310 pathogenic Aortic aneurysm, familial thoracic 6 2023-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the ACTA2 protein (p.Arg39Cys). This variant is present in population databases (rs112901682, gnomAD 0.03%). This missense change has been observed in individuals with aortopathy (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000143866 SCV000902099 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-07-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital Muenster RCV002274892 SCV002562231 pathogenic See cases 2022-07-18 criteria provided, single submitter clinical testing ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5,BP1
Ambry Genetics RCV000143866 SCV002624318 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-09-17 criteria provided, single submitter clinical testing The p.R39C variant (also known as c.115C>T), located in coding exon 1 of the ACTA2 gene, results from a C to T substitution at nucleotide position 115. The arginine at codon 39 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD), and co-segregation in affected relatives was reported in two unrelated families (Hoffjan S et al. Eur. J. Hum. Genet., 2011 May;19:520-4; Renard M et al. Int. J. Cardiol., 2013 May;165:314-21; Regalado ES et al. Am. J. Med. Genet. A, 2014 Jan;164A:106-12; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). Alternate amino acid substitutions at this position, p.R39H and p.R39G, have also been associated with TAAD and vascular disease findings (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27; Regalado ES et al. Circ Cardiovasc Genet. 2015;8(3):457-64). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000490091 SCV004564421 pathogenic not provided 2023-02-15 criteria provided, single submitter clinical testing The ACTA2 c.115C>T; p.Arg39Cys variant (rs112901682) is reported in multiple individuals with thoracic aortic disorders and shown to segregate with disease in affected family members (Campens 2015, Hoffjan 2011, Kaw 2022, Li 2021, Overwater 2018). This variant is also reported in ClinVar (Variation ID: 65449). This variant is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.853). Additionally, other variants at this codon (p.Arg39Gly, p.Arg39His) are reported in individuals with aortic aneurysm and dissection and are considered to be causative (Hoffjan 2011, Overwater 2018, Regalado 2015). Based on available information, the p.Arg39Cys variant is considered to be pathogenic. References: Campens L et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015 Feb 3;10:9. PMID: 25644172. Hoffjan S et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011 May;19(5):520-4. PMID: 21248741. Kaw A et al. Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. Am J Med Genet A. 2022 Aug;188(8):2389-2396. PMID: 35567597. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Regalado ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435.
OMIM RCV000055647 SCV000083872 not provided Aortic aneurysm, familial thoracic 6 2024-02-08 no assertion criteria provided literature only
Blueprint Genetics RCV000143866 SCV000188734 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2014-01-30 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000490091 SCV001807981 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000490091 SCV001953652 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.