Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000766262 | SCV000320481 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2020-04-07 | criteria provided, single submitter | clinical testing | The p.Y364C variant (also known as c.1091A>G), located in coding exon 8 of the SMAD3 gene, results from an A to G substitution at nucleotide position 1091. The tyrosine at codon 364 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in several patients with vascular disease and has been reported to segregate with disease in one family (Schepers D et al. Hum. Mutat., 2018 05;39:621-634; Renner S et al. Genet. Med., 2019 08;21:1832-1841; Ambry internal data; B. Loeys pers. comm.). 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. |
| Institute of Human Genetics, |
RCV000766262 | SCV000897682 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-11-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000766262 | SCV002197920 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with cysteine at codon 364 of the SMAD3 protein (p.Tyr364Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMAD3-related conditions (PMID: 29392890, 30675029). ClinVar contains an entry for this variant (Variation ID: 264500). 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 SMAD3 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |