Submissions for variant NM_000334.4(SCN4A):c.3917G>A (p.Gly1306Glu)

dbSNP: rs80338792

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489251	SCV000576821	pathogenic	not provided	2021-12-13	criteria provided, single submitter	clinical testing	Observed in multiple unrelated individuals with myotonia in the published literature (Furby et al. 2014; Lion-Francois et al., 2010; Singh et al., 2014); Published functional studies demonstrate a damaging effect as electrophysiological studies showed that G1306E reduced fast inactivation of the channel, as well as delayed channel opening and activation (Lerche et al., 1993; Mitrovic et al., 1995); 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; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Different missense changes at this residue (G1306V) and (G1306A) have been reported in the Human Gene Mutation Database and in the published literature (HGMD; Lerche et al., 1993; Ricker et al., 1994; Lion-Francois et al., 2010; Lampe et al., 2004; McClatchey et al., 1992); This variant is associated with the following publications: (PMID: 20713951, 8308722, 7473241, 16392038, 18723887, 25311598, 25088311, 30611854, 32849172, 32593548, 33084218, 26080010, 16832098, 26834636, 7980103, 23958773, 22016737, 23052413, 20237798, 28199958, 18166706, 29899727, 11723275, 20590641, 26944947, 20076800, 32010054)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552020	SCV000658570	pathogenic	Familial hyperkalemic periodic paralysis	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1306 of the SCN4A protein (p.Gly1306Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SCN4A-related conditions (PMID: 8308722, 16832098, 20713951, 25088311, 25311598, 26944947). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5920). 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 not expected to disrupt SCN4A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7980103, 8308722, 26080010). 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	RCV000489251	SCV002020021	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001823093	SCV002072972	pathogenic	Potassium-aggravated myotonia		criteria provided, single submitter	clinical testing	The missense variant p.G1306E in SCN4A (NM_000334.4) has been previously reported in heterozygous state in affected individuals (Singh RR et al; Lion-Francois L).Functional studies suggest a damaging effect (Groome JR et al). A different missense substitution at this codon (p.Gly1306Ala) has been determined to be pathogenic (Torbergsen T et al). The variant has been submitted to ClinVar as Pathogenic. The p.G1306E variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1306E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1306 of SCN4A is conserved in all mammalian species. The nucleotide c.3917 in SCN4A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000489251	SCV002498322	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SCN4A: PS4, PM2, PM5, PS3:Moderate, PP3, PP4
Molecular Genetics, Royal Melbourne Hospital	RCV002225070	SCV002503661	pathogenic	Paramyotonia congenita of Von Eulenburg	2020-06-26	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace glycine with glutamic acid at codon 1306 of the SCN4A protein (p.(Gly1306Glu)). The glycine residue is very highly conserved (100 vertebrates, UCSC), and is in the cytoplasmic ion transporter region, with a critical role in sodium channel inactivation (PM1, refer to OMIM #603967). There is a moderate physicochemical difference between glycine and glutamic acid. The variant is absent in a large population cohort (PM2, gnomAD v2.1.1 and v3). This variant has been previously reported in over 25 probands with myotonia (PS4, PMID 8308722, 23958773, 20713951, 16832098, 29774303, 25311598, 20076800, 29606556) and segregates with phenotype (PP1, PMID 16832098, 29774303). It has been reported as a de novo change in at least 12 families (PM6_VeryStrong, PMID 23958773, 20713951, 29774303). Functional studies support pathogenicity of the variant (PS3_Supporting, PMID 16392038, 30611854). Muscle biopsy studies demonstrate that p.(Gly1306Glu) affects electrophysiology (PMID 8308722). Multiple lines of computational evidence have conflicting predictions for the missense substitution. A different amino acid change at the same residue has been reported in three families with myotonia fluctuans (PMID 7980103). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant has been classified as PATHOGENIC. The following criteria have been applied: PM6_VeryStrong, PS4, PM1, PM2, PP1, PS3_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV002490328	SCV002782206	pathogenic	Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Familial hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16	2022-05-03	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000489251	SCV005198148	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786240	SCV005399169	pathogenic	SCN4A-related myopathy, autosomal recessive	2021-05-06	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 SCNA4-related disorders. Functional studies of missense variants have demonstrated both a loss and gain of protein function, even for the same phenotype (OMIM). (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 in congential myasthenic syndrome have been reported (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 glycine to glutamic acid (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid change at the same position has been observed in gnomAD (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated sodium-channel gate (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. At least 30 individuals from 24 families have been reported to harbour this variant, the majority of which arose de novo. This variant has also been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 32509969). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV001799588	SCV000026465	pathogenic	Myotonia permanens	2006-07-11	no assertion criteria provided	literature only