Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002230762 | SCV000543737 | uncertain significance | Juvenile polyposis syndrome | 2023-07-25 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 405485). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. 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. This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 300 of the SMAD4 protein (p.His300Arg). This variant is not present in population databases (gnomAD no frequency). |
| Gene |
RCV001538748 | SCV001756440 | uncertain significance | not provided | 2020-07-28 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Ambry Genetics | RCV002374754 | SCV002683722 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2020-09-24 | criteria provided, single submitter | clinical testing | The p.H300R variant (also known as c.899A>G), located in coding exon 6 of the SMAD4 gene, results from an A to G substitution at nucleotide position 899. The histidine at codon 300 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |