Submissions for variant NM_000334.4(SCN4A):c.3404G>A (p.Arg1135His)

dbSNP: rs527236150

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254971	SCV000322223	pathogenic	not provided	2018-11-05	criteria provided, single submitter	clinical testing	The R1135H pathogenic variant in the SCN4A gene has been reported previously in the heterozygous state in individuals with hypokalaemic periodic paralysis (Matthews et al., 2009; Sung et al., 2012; Cheng et al., 2011). Functional studies done on muscle fibers from a patient harboring the R1135H pathogenic variant showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis, in addition amplitude and rise time of action potentials were reduced compared with controls (Groome et al., 2014). Expression of R1135H in mammalian cells indicate gating defects that include significantly enhanced entry into inactivation and prolonged recovery (Groome et al., 2014). The R1135H variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1135H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1135H as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797599	SCV000937164	pathogenic	Hyperkalemic periodic paralysis	2024-04-15	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 1135 of the SCN4A protein (p.Arg1135His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 19118277, 21841462, 23516313, 24549961). In at least one individual the variant was observed to be de novo. This variant is also known as 3481A_x0005_>G. ClinVar contains an entry for this variant (Variation ID: 143201). 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) performed at Invitae 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: 24549961). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000254971	SCV001249365	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000254971	SCV001879494	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3481A>G. This variant has been found in several individuals with hypokalemic periodic paralysis, including de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate that this variant interferes with normal sodium channel function (PMID: 24549961). The variant is located in a region that is considered important for protein function and/or structure.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000132737	SCV002764873	pathogenic	Hypokalemic periodic paralysis, type 2	2020-12-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000132737	SCV005398031	pathogenic	Hypokalemic periodic paralysis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN4A-related disease. Functional studies of missense variants have demonstrated both loss- and gain of protein function effects, even for the same phenotype (OMIM, PMID: 24549961). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have been reported (PMID: 24549961, OMIM). (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 (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygote). (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 DIII of the S4 voltage sensor domain (PMID: 24549961). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. An alternative change (p.Arg1135Cys) has been reported in a homozygote individual with hypokalemic periodic paralysis (PMID: 24549961), and another alternative change (p.Arg1135Ser) has been reported as likely pathogenic and de novo (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in both de novo individuals and familial cases with hypokalemic periodic paralysis (ClinVar, PMID: 23516313, PMID: 19118277, PMID: 24549961, PMID: 21841462). (SP) 0903 - This variant has limited evidence for segregation with disease (PMID: 24549961). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis using patient muscle fibres found this variant caused reduced action potential maximums (PMID: 24549961). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005016463	SCV005651746	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	2024-01-10	criteria provided, single submitter	clinical testing
GeneReviews	RCV000132737	SCV000187698	not provided	Hypokalemic periodic paralysis, type 2		no assertion provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002305449	SCV002600045	pathogenic	Hypokalemic periodic paralysis, type 1	2022-04-12	no assertion criteria provided	research