Submissions for variant NM_001330260.2(SCN8A):c.4423G>A (p.Gly1475Arg)

dbSNP: rs796053216

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189277	SCV000242909	pathogenic	not provided	2020-05-19	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29235621, 30776697, 27864847, 29128679, 28923014, 29429461, 30171078, 30615093, 31402610, 32090326, 32040247)
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000416962	SCV000494529	likely pathogenic	Epileptic encephalopathy	2016-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000462091	SCV000544813	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1475 of the SCN8A protein (p.Gly1475Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27864847, 28923014, 30171078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207119). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN8A protein function. Experimental studies have shown that this missense change affects SCN8A function (PMID: 30615093). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000500598	SCV000596983	likely pathogenic	Developmental and epileptic encephalopathy, 13	2015-10-29	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000627041	SCV000747746	likely pathogenic	Epilepsy	2017-11-06	criteria provided, single submitter	clinical testing	This variant was identified in a mosaic state in a young female patient with epilepsy.
3billion	RCV000500598	SCV002058693	pathogenic	Developmental and epileptic encephalopathy, 13	2022-01-03	criteria provided, single submitter	clinical testing	he variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207119, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.75, 3CNET: 0.972, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 13 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000189277	SCV002545036	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	SCN8A: PM1, PM2, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting