Submissions for variant NM_001330260.2(SCN8A):c.3563G>A (p.Arg1188Gln)

dbSNP: rs1555226375

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000536288	SCV000633960	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1188 of the SCN8A protein (p.Arg1188Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN8A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 461339). 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.
GeneDx	RCV002282211	SCV002571562	likely pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be in the cytoplasmic loop between the second and third homologous domains; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002456092	SCV002615574	uncertain significance	Inborn genetic diseases	2018-11-21	criteria provided, single submitter	clinical testing	The p.R1188Q variant (also known as c.3563G>A), located in coding exon 18 of the SCN8A gene, results from a G to A substitution at nucleotide position 3563. The arginine at codon 1188 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003448318	SCV004176401	likely pathogenic	Developmental and epileptic encephalopathy, 13	2023-03-01	criteria provided, single submitter	clinical testing	The missense variant c.3563G>A (p.Arg1188Gln) in the SCN8A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. In in-vitro studies, algorithms were developed to predict the effect of sequence changes on RNA splicing suggesting that this variant may create or strengthen a splice site. This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Likely Pathogenic/Uncertain significance. The amino acid Arginine at position 1188 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg1188Gln in SCN8A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic