Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000499005 | SCV000590029 | uncertain significance | not provided | 2017-05-18 | criteria provided, single submitter | clinical testing | The E435A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). E435A is a 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV000705692 | SCV000834701 | uncertain significance | Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 | 2023-08-24 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs201396897, gnomAD 0.0009%). 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 SCN9A protein function. ClinVar contains an entry for this variant (Variation ID: 432313). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 435 of the SCN9A protein (p.Glu435Ala). |