Submissions for variant NM_000334.4(SCN4A):c.1378G>A (p.Glu460Lys)

gnomAD frequency: 0.00002  dbSNP: rs540596321

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001288737	SCV001476053	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002486087	SCV002792301	uncertain significance	Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16	2022-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537979	SCV003022572	uncertain significance	Hyperkalemic periodic paralysis	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 460 of the SCN4A protein (p.Glu460Lys). This variant is present in population databases (rs540596321, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of SCN4A-related conditions (PMID: 36796140). ClinVar contains an entry for this variant (Variation ID: 994951). Invitae Evidence 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 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 SCN4A protein function. 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.
Revvity Omics, Revvity	RCV001288737	SCV003818738	uncertain significance	not provided	2019-10-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490168	SCV004241540	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: SCN4A c.1378G>A (p.Glu460Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 1613940 control chromosomes (gnomAD v4). c.1378G>A has been reported in the literature in unspecified individuals affected with neurological disorders, details of the condition however was not provided (example, Vivekanandam_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Acetazolamide-Responsive Myotonia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36796140). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001288737	SCV005412807	uncertain significance	not provided	2024-08-09	criteria provided, single submitter	clinical testing	PP3