Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000704710 | SCV000833669 | uncertain significance | Juvenile polyposis syndrome | 2021-06-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 97 of the SMAD4 protein (p.Arg97His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SMAD4-related disease. This variant is not present in population databases (ExAC no frequency). |
| Ambry Genetics | RCV002440531 | SCV002750952 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2019-11-19 | criteria provided, single submitter | clinical testing | The p.R97H variant (also known as c.290G>A), located in coding exon 2 of the SMAD4 gene, results from a G to A substitution at nucleotide position 290. The arginine at codon 97 is replaced by histidine, an amino acid with highly similar properties. 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 alteration remains unclear. |