Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001582050 | SCV001818688 | uncertain significance | not provided | 2019-03-21 | 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect |
| Ambry Genetics | RCV003298942 | SCV004007144 | uncertain significance | Inborn genetic diseases | 2023-03-24 | criteria provided, single submitter | clinical testing | The p.R443P variant (also known as c.1328G>C), located in coding exon 4 of the SMAD6 gene, results from a G to C substitution at nucleotide position 1328. The arginine at codon 443 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. 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. |
| Mayo Clinic Laboratories, |
RCV001582050 | SCV004227435 | uncertain significance | not provided | 2023-02-22 | criteria provided, single submitter | clinical testing | PM2_supporting |
| Labcorp Genetics |
RCV003533012 | SCV004300470 | uncertain significance | Aortic valve disease 2 | 2023-07-27 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1214316). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 443 of the SMAD6 protein (p.Arg443Pro). 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 SMAD6 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. |