Submissions for variant NM_000334.4(SCN4A):c.3917G>T (p.Gly1306Val)

dbSNP: rs80338792

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479620	SCV000567468	pathogenic	not provided	2021-05-13	criteria provided, single submitter	clinical testing	Reported previously as a heterozygous variant in two unrelated families with paramyotonia congenita (McClatchey et al., 1992); Functional studies suggest that G1306V results in slower inactivation of the SCN4A sodium channel (Lerche et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 8308722, 1310898, 27415035, 26944947, 18337100, 18337730, 28150151, 26885337, 26080010, 22094069, 20445432, 17823953, 16832098, 8044656, 16392038, 7473241, 32849172, 32660787)
Athena Diagnostics	RCV000479620	SCV000615092	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with paramyotonia congenita in multiple families, and is reported in multiple other unrelated individuals with non-dystrophic myotonia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies indicate that this variant disrupts normal ion channel properties, resulting in aberrant channel regulation of current and signaling (PMID: 7473241, 16392038).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690377	SCV000818060	pathogenic	Hyperkalemic periodic paralysis	2024-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Val). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individuals with paramyotonia congenita (PMID: 1310898, 8044656, 8308722, 17823953, 18337100, 18337730, 20445432, 22094069, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5903). 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 95%. 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, 16832098, 20713951, 25088311, 25311598, 26080010, 26885337, 26944947). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000479620	SCV001249362	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000690377	SCV001370154	pathogenic	Hyperkalemic periodic paralysis	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3.
MGZ Medical Genetics Center	RCV000006264	SCV002581212	pathogenic	Paramyotonia congenita of Von Eulenburg	2021-10-25	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000006264	SCV003841909	pathogenic	Paramyotonia congenita of Von Eulenburg	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005903). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 27415035). Different missense changes at the same codon (p.Gly1306Ala, p.Gly1306Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005908, VCV000005920). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000479620	SCV005413269	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PM5, PS4
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000006265	SCV005418959	pathogenic	Potassium-aggravated myotonia		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PM5_Strong+PP3_Moderate
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000006264	SCV005438226	pathogenic	Paramyotonia congenita of Von Eulenburg	2024-12-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016246	SCV005651723	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	2024-06-05	criteria provided, single submitter	clinical testing
OMIM	RCV000006264	SCV000026446	pathogenic	Paramyotonia congenita of Von Eulenburg	2009-05-01	no assertion criteria provided	literature only
OMIM	RCV000006265	SCV000026447	pathogenic	Potassium-aggravated myotonia	2009-05-01	no assertion criteria provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267601	SCV002549812	pathogenic	SCN4A-related non-dystrophic myotonia	2022-04-06	no assertion criteria provided	research