Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002443380 | SCV002612334 | uncertain significance | Inborn genetic diseases | 2022-09-28 | criteria provided, single submitter | clinical testing | The p.E378K variant (also known as c.1132G>A), located in coding exon 4 of the SMAD6 gene, results from a G to A substitution at nucleotide position 1132. The glutamic acid at codon 378 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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. |
| Labcorp Genetics |
RCV003647871 | SCV004556889 | uncertain significance | Aortic valve disease 2 | 2023-04-22 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 1728885). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. This variant is present in population databases (rs751622656, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 378 of the SMAD6 protein (p.Glu378Lys). |