Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235703 | SCV000292970 | uncertain significance | not provided | 2015-07-17 | criteria provided, single submitter | clinical testing | The Y341C variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Y341C variant 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 conserved position between the S5 and S6 transmembrane segments of the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants have not been reported in this region of the protein in association with SCN9A-related neuropathy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant. |
| Invitae | RCV000538607 | SCV000649260 | 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 has not been reported in the literature in individuals affected with SCN9A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 341 of the SCN9A protein (p.Tyr341Cys). ClinVar contains an entry for this variant (Variation ID: 245823). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. |
| Ambry Genetics | RCV002518432 | SCV003568165 | uncertain significance | Inborn genetic diseases | 2021-08-02 | criteria provided, single submitter | clinical testing | The c.1022A>G (p.Y341C) alteration is located in exon 9 (coding exon 8) of the SCN9A gene. This alteration results from a A to G substitution at nucleotide position 1022, causing the tyrosine (Y) at amino acid position 341 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |