Submissions for variant NM_001330260.2(SCN8A):c.4447G>A (p.Glu1483Lys)

dbSNP: rs879255652

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001293365	SCV001481817	pathogenic	Epilepsy	2021-02-25	criteria provided, single submitter	clinical testing	The variant chr12-52184209-G-A, SCN8A(NM_014191.4):c.4447G>A,p.(Glu1483Lys) was identified in an individual with Epilepsy. Inheritance was maternal (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Pathogenic (criteria: PP1_Strong, PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3_Supporting).
GeneDx	RCV001556220	SCV001777757	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect indicating that the E1483K variant alters sodium channel properties (Liu et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 32090326, 30615093, 27210545, 27270488, 26677014, 30185235, 29263050, 31904124, 26029160)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518547	SCV003286785	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1483 of the SCN8A protein (p.Glu1483Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SCN8A-related conditions (PMID: 26677014, 30185235). It has also been observed to segregate with disease in related individuals. This variant is also known as p.E1442K. ClinVar contains an entry for this variant (Variation ID: 253195). 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 SCN8A protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN8A function (PMID: 30615093). For these reasons, this variant has been classified as Pathogenic.
University of British Columbia, BC Children's Hospital	RCV000239671	SCV004031480	pathogenic	Seizures, benign familial infantile, 5	2023-08-30	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000239671	SCV005368189	pathogenic	Seizures, benign familial infantile, 5	2022-03-18	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000239671	SCV005416328	pathogenic	Seizures, benign familial infantile, 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Moderate+PP2+PS4_Moderate+PP1_Strong+PP4
OMIM	RCV000239671	SCV000297995	pathogenic	Seizures, benign familial infantile, 5	2016-08-22	no assertion criteria provided	literature only
GeneReviews	RCV002226427	SCV002505395	not provided	Developmental and epileptic encephalopathy, 13		no assertion provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV003992245	SCV004809328	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only