Submissions for variant NM_000334.4(SCN4A):c.3938C>T (p.Thr1313Met)

dbSNP: rs121908547

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414134	SCV000491055	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as T1313M alters channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a common pathogenic variant associated with paramyotonia congenita; This variant is associated with the following publications: (PMID: 8583225, 27199537, 8910215, 8740371, 29790872, 11054753, 32083589, 1310898, 27415035, 12872329, 10206477, 9130156, 7533571, 28877545, 30611854, 31567646, 32849172, 32670189, 33430134, 21220685, 30647473, 15318338, 7809121, 32660787)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000006266	SCV000584111	pathogenic	Paramyotonia congenita of Von Eulenburg	2016-01-14	criteria provided, single submitter	research
Athena Diagnostics	RCV000414134	SCV000615094	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in individuals with paramyotonia congenita and segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7809121, 8740371, 30611854, 33430134)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540455	SCV000658572	pathogenic	Hyperkalemic periodic paralysis	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1313 of the SCN4A protein (p.Thr1313Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant paramyotonia congenita (PMID: 1310898, 8044656, 14518676, 15790667, 18166706, 18337730, 19770477, 20445432, 21220685, 23771340, 23810313, 26834636, 27199537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5904). 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: 7809121, 8910215). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763019	SCV000893470	pathogenic	Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414134	SCV002020028	pathogenic	not provided	2019-03-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000006266	SCV002579949	pathogenic	Paramyotonia congenita of Von Eulenburg	2022-05-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532297	SCV004120550	pathogenic	SCN4A-related disorder	2023-02-03	criteria provided, single submitter	clinical testing	The SCN4A c.3938C>T variant is predicted to result in the amino acid substitution p.Thr1313Met. This variant has been reported in many individuals to be causative for paramyotonia congenita (McClatchey et al. 1992. PubMed ID: 1310898; Matthews et al. 2011. PubMed ID: 21220685). Functional studies suggest that the p.Thr1313Met substitution causes a disturbance in sodium channel inactivation (Yang et al. 1994. PubMed ID: 7809121). A different substitution at the same amino acid (p.Thr1313Ala) has also been observed in a patient with paramyotonia congenita, and may induce defects in sodium channel inactivation (Bouhours et al. 2003. PubMed ID: 14617673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-62021185-G-A). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003455986	SCV004183512	pathogenic	Congenital myasthenic syndrome 16	2023-10-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786239	SCV005398715	pathogenic	SCN4A-related myopathy, autosomal recessive	2022-02-02	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 (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. 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 threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 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 putative hydrophobic latch of the annotated sodium channel gate domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most frequently reported variants in individuals with paramyotonia congenita (ClinVar, PMID: 30647473, 32849172, 33430134). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000006266	SCV000026448	pathogenic	Paramyotonia congenita of Von Eulenburg	2011-01-01	no assertion criteria provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267602	SCV002549797	pathogenic	SCN4A-related non-dystrophic myotonia	2022-04-06	no assertion criteria provided	research