Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000823222 | SCV000319815 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-03-30 | criteria provided, single submitter | clinical testing | The p.P124L variant (also known as c.371C>T), located in coding exon 2 of the SMAD3 gene, results from a C to T substitution at nucleotide position 371. The proline at codon 124 is replaced by leucine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV000823222 | SCV000964073 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-03-23 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 264116). This variant disrupts the p.Pro124 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 27986426), which suggests that this may be a clinically significant amino acid residue. This missense change has been observed in individual(s) with SMAD3-related disease (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 124 of the SMAD3 protein (p.Pro124Leu). 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. |