Submissions for variant NM_001330260.2(SCN8A):c.3979A>G (p.Ile1327Val)

dbSNP: rs879255704

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493549	SCV000583186	likely pathogenic	not provided	2015-10-29	criteria provided, single submitter	clinical testing	The I1327V variant in the SCN8A gene has been reported previously in the heterozygous state in an individual with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders (Vaher et al., 2014). The I1327 variant has also been reported in the heterozygous state in an unrelated individual with in utero onset movement disorder, epileptic encephalopahy, and developmental delay (Singh et al., 2015). The I1327V variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the predicted S5 transmembrane segment of third homologous domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I1327V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The I1327V variant is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc	RCV000493549	SCV002817220	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing	This variant occurs de novo in an individual tested at Athena Diagnostics and in published literature (PMID: 26993267, 24352161, 25799905). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests that this variant alters the voltage-gated sodium channel (PMID: 27375106).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Invitae	RCV002519872	SCV003441260	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-10-05	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects SCN8A function (PMID: 27375106). 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. ClinVar contains an entry for this variant (Variation ID: 253288). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 24352161, 25799905, 26993267). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1327 of the SCN8A protein (p.Ile1327Val). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335289	SCV004046325	pathogenic	SCN8A-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo heterozygous change and as a heterozygous change of unknown inheritance in several individuals with SCN8A-related early-infantile epileptic encephalopathy (PMID: 24352161, 25799905, 31010614, 30078772, 26993267, 33915942). In-vitro functional studies showed that the p.Ile1327Val variant leads to an impaired channel inactivation suggesting a gain-of-function effect (PMID: 24352161, 27375106). The p.Ile1327Val variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3979A>G (p.Ile1327Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3979A>G (p.Ile1327Val) variant is classified as Pathogenic.
GeneReviews	RCV000239751	SCV000298199	not provided	Developmental and epileptic encephalopathy, 13		no assertion provided	literature only