Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001991338 | SCV002287114 | likely pathogenic | Juvenile polyposis syndrome | 2022-03-08 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 533 of the SMAD4 protein (p.Leu533Pro). 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. This variant disrupts the p.Leu533 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been observed in individuals with SMAD4-related conditions (PMID: 15031030, 20101697), which suggests that this may be a clinically significant amino acid residue. 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 SMAD4 protein function. This missense change has been observed in individuals with clinical features of juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia (PMID: 20101697; Invitae). This variant is not present in population databases (gnomAD no frequency). |