Submissions for variant NM_001330260.2(SCN8A):c.3967G>A (p.Ala1323Thr)

dbSNP: rs794727361

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176314	SCV000227948	pathogenic	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001095653	SCV001251408	likely pathogenic	Cognitive impairment with or without cerebellar ataxia	2019-10-15	criteria provided, single submitter	clinical testing
Invitae	RCV001219444	SCV001391383	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1323 of the SCN8A protein (p.Ala1323Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 29100083, 33201365; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 195688). 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 expected to disrupt SCN8A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253356	SCV001429028	likely pathogenic	Developmental and epileptic encephalopathy, 13	2018-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000176314	SCV001769668	pathogenic	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the Intracellular loop between the S4 and S5 transmembrane segments of the third homologous domain; This variant is associated with the following publications: (PMID: 29100083, 32090326, 33201365, 35325842, 34979445)
MGZ Medical Genetics Center	RCV001253356	SCV002579567	likely pathogenic	Developmental and epileptic encephalopathy, 13	2022-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321698	SCV002626319	likely pathogenic	Inborn genetic diseases	2018-01-29	criteria provided, single submitter	clinical testing	The p.A1323T variant (also known as c.3967G>A), located in coding exon 21 of the SCN8A gene, results from a G to A substitution at nucleotide position 3967. The alanine at codon 1323 is replaced by threonine, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with focal epilepsy (Ambry internal data). An alternate amino acid substitution at this position, p.A1323S, has been reported as de novo in an individual with early infantile epileptic encephalopathy; however, clinical details were limited (Trump N et al. J. Med. Genet., 2016 May;53:310-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001253356	SCV001943318	pathogenic	Developmental and epileptic encephalopathy, 13		no assertion criteria provided	clinical testing