Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001051043 | SCV000739668 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2019-08-06 | criteria provided, single submitter | clinical testing | The p.G245R variant (also known as c.733G>C), located in coding exon 6 of the SMAD3 gene, results from a G to C substitution at nucleotide position 733. The glycine at codon 245 is replaced by arginine, an amino acid with dissimilar properties. This alteration was previously reported in a nonsyndromic pediatric patient with a dilated aorta (Arroyave J et al. Cardiol Young, 2018;28:765-767). Internal structural analysis indicates that this variant causes a significant decrease in SMAD3 structural stability (Qin BY et al. Genes Dev. 2002 Aug;16(15):1950-63; Ambry internal data). A likely pathogenic alteration resulting in the same amino acid change (c.733G>A p.G245R) has also been described (Aubart M. PLoS ONE 2014; 9(5):e96387). 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. |
| Invitae | RCV001051043 | SCV001215176 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 245 of the SMAD3 protein (p.Gly245Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 24804794, 29444731; Invitae). ClinVar contains an entry for this variant (Variation ID: 520179). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |