Submissions for variant NM_000334.4(SCN4A):c.1583G>T (p.Ser528Ile)

gnomAD frequency: 0.00004  dbSNP: rs906634749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064203	SCV001229087	uncertain significance	Hyperkalemic periodic paralysis	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 528 of the SCN4A protein (p.Ser528Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant SCN4A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 858350). 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 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.
Fulgent Genetics, Fulgent Genetics	RCV002497456	SCV002814267	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	2022-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002553953	SCV003547393	uncertain significance	Inborn genetic diseases	2022-05-16	criteria provided, single submitter	clinical testing	The c.1583G>T (p.S528I) alteration is located in exon 10 (coding exon 10) of the SCN4A gene. This alteration results from a G to T substitution at nucleotide position 1583, causing the serine (S) at amino acid position 528 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001064203	SCV003807966	uncertain significance	Hyperkalemic periodic paralysis	2022-03-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated
Revvity Omics, Revvity	RCV003142011	SCV003818713	uncertain significance	not provided	2020-03-25	criteria provided, single submitter	clinical testing