Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001765823 | SCV002000479 | uncertain significance | not provided | 2021-04-14 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function |
Labcorp Genetics |
RCV003120678 | SCV003784835 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-05-25 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 262 of the SMAD3 protein (p.Asp262Asn). This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. 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 disrupts the p.Asp262 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt SMAD3 protein function. ClinVar contains an entry for this variant (Variation ID: 1314782). |
All of Us Research Program, |
RCV004009027 | SCV004829708 | uncertain significance | Aneurysm-osteoarthritis syndrome | 2023-08-08 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with asparagine at codon 262 of the SMAD3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD3-related disorders in the literature. This variant has not been identified 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. |