Submissions for variant NM_000334.4(SCN4A):c.4352G>A (p.Arg1451His)

dbSNP: rs748517635

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV002473036	SCV000615100	uncertain significance	not provided	2021-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532008	SCV000658580	pathogenic	Hyperkalemic periodic paralysis	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1451 of the SCN4A protein (p.Arg1451His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant SCN4A-related conditions (PMID: 27922499, 35907044; internal data). ClinVar contains an entry for this variant (Variation ID: 448280). 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 80%. This variant disrupts the p.Arg1451 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29391559, 29946067). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV002473036	SCV003818667	uncertain significance	not provided	2021-09-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000532008	SCV005400089	uncertain significance	Hyperkalemic periodic paralysis	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function (LoF) and gain of function (GoF) are known mechanisms of disease in this gene and are associated with SCN4A-related disease. GoF is a well characterised disease mechanism for autosomal dominant SCN4A-related diseases, while LoF is a mechanism associated with autosomal recessive SCN4A-related diseases (PMID: 26700687, OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Phenotypes involving paralysis and myotonia are typically inherited in a dominant manner, whereas myasthenic syndrome and congenital myopathy display recessive inheritance (OMIM, PMID: 26700687). (I) 0115 - Variants in this gene are known to have variable expressivity. Some individuals carrying pathogenic variants do not present with a typical clinical phenotype, however they do have detectable signs of myotonia on EMG (PMID: 20301669). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transport protein domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes have been observed in at least five individuals in the literature with SCN4A-related conditions. This includes several affected heterozygotes, and one homozygote who was affected with hypokalemic periodic paralysis (PMIDs: 29946067, 29391559). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by two clinical laboratories in ClinVar, and was observed in an individual with hyperkalemia and gait abnormalitites who was homozygous for this variant. This variant has also been observed as heterozygous in one individual in the literature who had a genetically confirmed diagnosis of myotonic dystrophy 2, in whom the SCN4A variant was thought to explain their severe muscle pain (PMID: 27922499). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267617	SCV002549803	likely pathogenic	SCN4A-related non-dystrophic myotonia	2022-04-06	no assertion criteria provided	research
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002305499	SCV002600047	pathogenic	Hypokalemic periodic paralysis, type 1	2022-04-12	no assertion criteria provided	research