Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000215951 | SCV000279873 | uncertain significance | not provided | 2016-09-27 | criteria provided, single submitter | clinical testing | The c.3289 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3289 A>G variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.3289 A>G may create a cryptic splice donor site in exon 17 which may supplant the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.3289 A>G does not alter splicing, it will result in the S1097G missense change, which is non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV002516204 | SCV003254480 | uncertain significance | Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 | 2023-08-04 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 234826). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is present in population databases (rs758165714, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1097 of the SCN9A protein (p.Ser1097Gly). 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 SCN9A 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. |