Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000431351 | SCV000534841 | uncertain significance | not provided | 2017-01-10 | criteria provided, single submitter | clinical testing | The R1337W variant in the SCN4A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1337W variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1337W 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 position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue, R1337P, has been reported in the heterozygous state in a patient with nondystrophic myotonia who was also heterozygous for a missense variant in the CLCN1 gene, which authors suggest had a modifying effect on the phenotype (Furby et al., 2014). We interpret R1337W as a variant of uncertain significance. |
| Invitae | RCV003505116 | SCV004245487 | uncertain significance | Hyperkalemic periodic paralysis | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1337 of the SCN4A protein (p.Arg1337Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 391710). 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 expected to disrupt SCN4A protein function with a positive predictive value of 95%. 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. |