Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001215527 | SCV001387277 | uncertain significance | Juvenile polyposis syndrome | 2023-03-02 | criteria provided, single submitter | clinical testing | This variant, c.1479_1481del, results in the deletion of 1 amino acid(s) of the SMAD4 protein (p.Asp494del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of juvenile polyposis syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 945003). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. |
| Ambry Genetics | RCV002393505 | SCV002701127 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2017-04-19 | criteria provided, single submitter | clinical testing | The c.1479_1481delTGA variant (also known as p.D494del) is located in coding exon 11 of the SMAD4 gene. This variant results from an in-frame TGA deletion at nucleotide positions 1479 to 1481. This results in the in-frame deletion of an aspartic acid at codon 494. This alteration was detected in an individual with clinical features suggestive of a combined juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Ambry internal data). This variant co-segregated with disease in one family tested in our laboratory. Based on internal structural analysis, this alteration destabilizes SMAD4 at its interface with SMAD2/3 (Chacko BM et al. Mol. Cell, 2004 Sep;15:813-23). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al., Bioinformatics 2015 Aug; 31(16):2745-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |