Submissions for variant NM_001330260.2(SCN8A):c.4850G>A (p.Arg1617Gln)

dbSNP: rs587777721

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000144154	SCV000297794	pathogenic	Developmental and epileptic encephalopathy, 13	2016-07-14	criteria provided, single submitter	research
GeneDx	RCV000522954	SCV000616869	pathogenic	not provided	2021-10-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in channel hyperactivity (Wagnon et al., 2016); 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 variant is associated with the following publications: (PMID: 31692161, 25785782, 24194747, 26029160, 23020937, 24888894, 25568300, 25046240, 28554332, 29588952, 30171078, 28191890, 29655203, 32090326, 31175295, 33004838, 33442870, 26900580)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636307	SCV000757746	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-24	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 1617 of the SCN8A protein (p.Arg1617Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathies (PMID: 23020937, 24888894, 25046240, 25568300, 25785782, 26029160, 29588952). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156106). 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%. Experimental studies have shown that this missense change affects SCN8A function (PMID: 26900580). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266283	SCV001444456	pathogenic	Inborn genetic diseases	2018-01-04	criteria provided, single submitter	clinical testing	The p.R1617Q pathogenic mutation (also known as c.4850G>A), located in coding exon 26 of the SCN8A gene, results from a G to A substitution at nucleotide position 4850. The arginine at codon 1617 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first identified in an individual with non-syndromic intellectual disability (Rauch A et al. Lancet, 2012 Nov;380:1674-82). It has also been reported in individuals with seizure disorders (Ohba C et al. Epilepsia, 2014 Jul;55:994-1000; Larsen J et al. Neurology, 2015 Feb;84:480-9; Kong W et al. Epilepsia, 2015 Mar;56:431-8; Dyment DA et al. Clin. Genet., 2015 Jul;88:34-40). In ND7/23 cells, this mutation causes elevated channel activity due to impaired channel inactivation (Wagnon JL et al. Ann Clin Transl Neurol, 2016 Feb;3:114-23). In addition, internal structural analysis indicates that this variant is part of a known motif needed for protein function and there are known pathogenic variants at equivalent positions in the protein (Spampanato J et al. J. Neurosci., 2004 Nov;24:10022-34; Mantegazza M et al. J. Neurosci., 2005 Mar;25:3341-9; Laezza F et al. Mol. Cell. Neurosci., 2009 Oct;42:90-101; Catterall WA. Neuron, 2010 Sep;67:915-28; Yan Z et al. Cell, 2017 Jul;170:470-482.e11). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000144154	SCV000189234	pathogenic	Developmental and epileptic encephalopathy, 13	2014-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000144154	SCV000298208	not provided	Developmental and epileptic encephalopathy, 13		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678845	SCV000805036	uncertain significance	developmental delay with seizures	2017-08-25	no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003992195	SCV004809225	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only