Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002342902 | SCV002644013 | uncertain significance | Inborn genetic diseases | 2022-10-17 | criteria provided, single submitter | clinical testing | The p.H339L variant (also known as c.1016A>T), located in coding exon 4 of the SMAD6 gene, results from an A to T substitution at nucleotide position 1016. The histidine at codon 339 is replaced by leucine, an amino acid with similar 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. |
| Labcorp Genetics |
RCV003102668 | SCV003460117 | uncertain significance | Aortic valve disease 2 | 2023-09-19 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1744530). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 339 of the SMAD6 protein (p.His339Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. 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. |