Submissions for variant NM_000334.4(SCN4A):c.1354G>A (p.Glu452Lys)

gnomAD frequency: 0.00006  dbSNP: rs372631097

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000688828	SCV000816452	uncertain significance	Hyperkalemic periodic paralysis	2023-12-14	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 452 of the SCN4A protein (p.Glu452Lys). This variant is present in population databases (rs372631097, gnomAD 0.02%). This missense change has been observed in individual(s) with non-dystrophic myotonia (PMID: 18337100, 29606556). ClinVar contains an entry for this variant (Variation ID: 568464). 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.
Illumina Laboratory Services, Illumina	RCV001127862	SCV001287218	likely benign	Potassium-aggravated myotonia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001127863	SCV001287219	uncertain significance	Congenital myasthenic syndrome 16	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001127864	SCV001287220	likely benign	Paramyotonia congenita of Von Eulenburg	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000688828	SCV001287221	likely benign	Hyperkalemic periodic paralysis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001127865	SCV001287222	likely benign	Hypokalemic periodic paralysis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001552589	SCV001773298	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	Reported in association with autosomal dominant non-dystrophic myotonia; however, functional characterization of the variant was not performed (Dupre et al., 2009); Reported in a patient with a skeletal muscle channelopathy; however, additional information was not provided (Stunnenberg et al., 2018); 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: 18337100, 29606556, 33325393, 36779057)
Ambry Genetics	RCV002544829	SCV003731626	uncertain significance	Inborn genetic diseases	2022-05-03	criteria provided, single submitter	clinical testing	The c.1354G>A (p.E452K) alteration is located in exon 9 (coding exon 9) of the SCN4A gene. This alteration results from a G to A substitution at nucleotide position 1354, causing the glutamic acid (E) at amino acid position 452 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (22/248866) total alleles studied. The highest observed frequency was 0.02% (3/15442) of African alleles. This alteration was reported in a family with myotonia, episodic weakness, muscle stiffness, and variable muscle hypertrophy (Dupré, 2009). This alteration was also reported in an additional unrelated individual with sodium channel myotonia/paramyotonia congenita (Stunnenberg, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001552589	SCV003821267	uncertain significance	not provided	2021-10-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001552589	SCV004562674	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535724	SCV001749823	not provided	Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-12-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000688828	SCV002600052	uncertain significance	Hyperkalemic periodic paralysis	2022-04-12	no assertion criteria provided	research