Submissions for variant NM_000334.4(SCN4A):c.2078T>G (p.Ile693Ser)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002625765	SCV002956470	likely pathogenic	Familial hyperkalemic periodic paralysis	2022-10-19	criteria provided, single submitter	clinical testing	This variant disrupts the p.Ile693 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2649440, 8902732, 9508833, 19015492, 20076800). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This missense change has been observed in individual(s) with autosomal dominant paramyotonia congenita (PMID: 28662944). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 693 of the SCN4A protein (p.Ile693Ser).