Submissions for variant NM_000334.4(SCN4A):c.3466G>A (p.Ala1156Thr)

gnomAD frequency: 0.00003  dbSNP: rs80338958

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516392	SCV000615084	likely pathogenic	not provided	2019-05-10	criteria provided, single submitter	clinical testing	The best available variant frequency is 3-10 times higher than the disease allele frequency, and data include at least 10 observations. Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004616	SCV001162774	pathogenic	Focal-onset seizure	2022-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020271	SCV001206949	pathogenic	Hyperkalemic periodic paralysis	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1156 of the SCN4A protein (p.Ala1156Thr). This variant is present in population databases (rs80338958, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant SCN4A-related disease (PMID: 1338909, 28330959). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5900). 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. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 28330959). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000516392	SCV001249364	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000516392	SCV002020027	pathogenic	not provided	2019-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000516392	SCV002520120	pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant results in altered channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994; Hayward et al., 1999; Palmio et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 7809121, 22016737, 10227633, 14501839, 22926674, 20076800, 16193245, 1338909, 28330959, 31440732, 32849172, 32619119)
MGZ Medical Genetics Center	RCV000020271	SCV002579821	likely pathogenic	Hyperkalemic periodic paralysis	2022-01-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496281	SCV002809749	pathogenic	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	2022-04-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162214	SCV003862265	pathogenic	Inborn genetic diseases	2023-03-08	criteria provided, single submitter	clinical testing	The c.3466G>A (p.A1156T) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a G to A substitution at nucleotide position 3466, causing the alanine (A) at amino acid position 1156 to be replaced by a threonine (T). _x000D_ _x000D_ The SCN4A c.3466G>A (p.A1156T) alteration is classified as pathogenic for autosomal dominant SCN4A-related myotonia and/or periodic paralysis disorders; however, its clinical significance for autosomal recessive SCN4A-related congenital myasthenic syndrome is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.005% (15/281704) total alleles studied. The highest observed frequency was 0.044% (11/25072) of European (Finnish) alleles. This alteration has been reported in multiple individuals and families with clinical features consistent with SCN4A-related myotonia and/or periodic paralysis disorders (McClatchey, 1992; Lee, 2009; Song, 2012; Palmio, 2017; Sainio, 2022). EMG myotonic discharges have been detected in multiple individuals with this variant (Palmio, 2017). Another alteration at the same codon, c.3466G>T (p.A1156S), has been described in an individual with sodium-channel myotonia (Maggi, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.A1156T alteration exhibited a disturbance in channel inactivation compared to the wild-type (Yang, 1994; Palmio, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545720	SCV004046438	pathogenic	SCN4A-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with paramyotonia congenita, hyperkalaemic periodic paralysis, exercise- and cold-induced muscle cramps, muscle stiffness, myalgia, and generalized seizures (PMID: 1338909, 28330959, 22926674, 31440732, 34418069). Different amino acid changes at the same residue (p.Ala1156Ser) have been previously reported in individuals with myotonia and periodic paralyses (PMID: 32849172). Functional studies showed that the c.3466G>A (p.Ala1156Thr) variant resulted in mild attenuation and disturbance of channel inactivation due to reduced macroscopic rate, accelerated recovery, and altered voltage dependence (PMID: 1338909, 7809121, 28330959). The c.3466G>A (p.Ala1156Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/281704) and thus is presumed to be rare. The c.3466G>A (p.Ala1156Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3466G>A (p.Ala1156Thr) variant is classified as Pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV004595874	SCV005088892	pathogenic	Potassium-aggravated myotonia	2021-03-30	criteria provided, single submitter	clinical testing	This variant was previously reported in a family of Finnish origin with incomplete penetrance and the members were reported with variable phenotypes, but it was found to be consistent with the features of HYPP, PMC, and myotonia [PMID: 1338909]. In addition, this variant was reported in multiple myalgia patients with clinical features of exercise- and cold-induced muscle cramps, muscle stiffness [PMID: 28330959] and also in two Korean patients exhibiting the myotonia and HYPP phenotypes, respectively [ PMID: 20076800]. Functional studies using invitro transfection assays showed fast inactivation in cells harboring variant p.A1156T channel was mildly attenuated in comparison to cells with wild-type channel suggesting the gain of function [PMID: 28330959]
OMIM	RCV000006260	SCV000026442	pathogenic	Paramyotonia congenita/hyperkalemic periodic paralysis	1992-10-01	no assertion criteria provided	literature only