Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001256143 | SCV001432931 | uncertain significance | Seizure | 2020-02-04 | criteria provided, single submitter | clinical testing | The c.5519G>A (p.Gly1840Asp) variant identified in the SCN9A gene of substitutes a completely conserved Glycine for Aspartic Acid at amino acid 1840/1978 (coding exon 27/27). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes; allele frequency: 1.19e-5). In silico algorithms predict this variant to be Deleterious (Provean; score: -6.55) and Damaging (SIFT; score:0.000) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Gly1840 residue is within the C-terminal cytosolic domain of SCN9A, and this region is not a known hotspot for pathogenic variants. Given the lack of compelling evidence for its pathogenicity, the c.5519G>A (p.Gly1840Asp) variant identified in the SCN9A gene is reported as a Variant of Uncertain Significance. |
| Invitae | RCV001350412 | SCV001544811 | uncertain significance | Neuropathy, hereditary sensory and autonomic, type 2A; Generalized epilepsy with febrile seizures plus, type 7 | 2023-01-19 | 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 SCN9A protein function. ClinVar contains an entry for this variant (Variation ID: 978182). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is present in population databases (rs757285775, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1840 of the SCN9A protein (p.Gly1840Asp). |