Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002310726 | SCV000213212 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2022-01-11 | criteria provided, single submitter | clinical testing | The p.I314V variant (also known as c.940A>G), located in coding exon 7 of the SMAD4 gene, results from an A to G substitution at nucleotide position 940. The isoleucine at codon 314 is replaced by valine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000462441 | SCV000543751 | uncertain significance | Juvenile polyposis syndrome | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 314 of the SMAD4 protein (p.Ile314Val). This variant is present in population databases (rs748622028, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 183879). 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. |
Color Diagnostics, |
RCV000162740 | SCV000686566 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-21 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 314 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has been identified in 1/251388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Sema4, |
RCV000162740 | SCV002538359 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-14 | criteria provided, single submitter | curation | |
Gene |
RCV002277319 | SCV002567629 | uncertain significance | not provided | 2022-08-17 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10636916) |
Baylor Genetics | RCV003474847 | SCV004202573 | uncertain significance | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 2023-10-16 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV002277319 | SCV004224490 | uncertain significance | not provided | 2022-04-19 | criteria provided, single submitter | clinical testing | BP5 |