Submissions for variant NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)

gnomAD frequency: 0.00002  dbSNP: rs377176361

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001200229	SCV001371133	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	SCN4A: PM1, PM2, PP1:Moderate, PS4:Moderate, PP3, PP4, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217902	SCV001389761	pathogenic	Hyperkalemic periodic paralysis	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1455 of the SCN4A protein (p.Ile1455Thr). This variant is present in population databases (rs377176361, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of proximal myopathy and paramyotonia congenita (PMID: 28024841). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932430). 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) indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 28024841). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001200229	SCV001476854	pathogenic	not provided	2022-09-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of myotonia. Additionally, in our internal patient population, this variant is statistically more frequent than in the general population. Assessment of experimental evidence suggests this variant results in abnormal protein function. Functional studies suggest complex effects on SCN4A caused by the variant, including slower current inactivation and decrease in overall current levels (PMID:28024841). The variant is located in a region that is considered important for protein function and/or structure.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001564044	SCV001787136	pathogenic	Paramyotonia congenita of Von Eulenburg	2021-06-18	criteria provided, single submitter	research	ACMG codes: PS3; PS4M; PM1; PM2; PP1S; PP3; PP5
Revvity Omics, Revvity	RCV001200229	SCV002019131	likely pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005005065	SCV002777364	pathogenic	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal	2024-05-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001200229	SCV003926173	likely pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate destabilization in the inactivated state which is a typical pathogenic mechanism for sodium channel myotonia and paramyotonia congenita (Bednarz et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29606556, 31127727, 28024841, 30420713)
Pars Genome Lab	RCV003229884	SCV003926610	likely benign	Hypokalemic periodic paralysis, type 2		flagged submission	clinical testing