Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000037195 | SCV000060852 | uncertain significance | not specified | 2019-07-03 | criteria provided, single submitter | clinical testing | Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ala140Val variant in ACTA2 is absent from gnomAD with adequate coverage. Computational predictors predict that the variant is damaging. The residue is entirely conserved and no species harbor the variant amino acid. It has been reported as pathogenic (2013) and Uncertain significance (2014) by two high-volume clinical labs. The variant has been reported in 1 LMM patient with TAAD (Lerner-Ellis 2014) and 1 additional TAAD patient (Overwater 2018). Both had family histories. |
| Gene |
RCV000211885 | SCV000233294 | uncertain significance | not provided | 2022-01-10 | criteria provided, single submitter | clinical testing | Has been reported as a variant of uncertain significance in a patient with TAAD in published literature (Lerner-Ellis, et al., 2014); 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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 44217; ClinVar); This variant is associated with the following publications: (PMID: 24793577, 29907982) |
| Invitae | RCV001852771 | SCV002225316 | likely pathogenic | Aortic aneurysm, familial thoracic 6 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the ACTA2 protein (p.Ala140Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of thoracic aortic aneurysm and dissection (TAAD) and/or thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 44217). 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 expected to disrupt ACTA2 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV000157091 | SCV002631495 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-10-20 | criteria provided, single submitter | clinical testing | The p.A140V variant (also known as c.419C>T), located in coding exon 4 of the ACTA2 gene, results from a C to T substitution at nucleotide position 419. The alanine at codon 140 is replaced by valine, an amino acid with similar properties. This alteration has been reported in individuals with thoracic aortic aneurysms and dissections (TAAD) and has demonstrated co-segregation with disease (Ambry internal data; GeneDx pers. comm.; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). This variant has also been detected in an individual with aortic dissections and in two of her family members, one with abdominal aortic rupture and one with abdominal aortic aneurysm (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Blueprint Genetics | RCV000157091 | SCV000206813 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2014-08-22 | no assertion criteria provided | clinical testing |