Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002917213 | SCV003249182 | uncertain significance | Aortic valve disease 2 | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 229 of the SMAD6 protein (p.Leu229Val). This variant is present in population databases (rs751084258, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 2042083). 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 with a negative predictive value of 80%. 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. |
| Ambry Genetics | RCV003274070 | SCV004007151 | uncertain significance | Inborn genetic diseases | 2023-04-24 | criteria provided, single submitter | clinical testing | The p.L229V variant (also known as c.685C>G), located in coding exon 1 of the SMAD6 gene, results from a C to G substitution at nucleotide position 685. The leucine at codon 229 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. 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. |
| Prevention |
RCV003403943 | SCV004105909 | uncertain significance | SMAD6-related disorder | 2022-09-16 | criteria provided, single submitter | clinical testing | The SMAD6 c.685C>G variant is predicted to result in the amino acid substitution p.Leu229Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-66996281-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |