Submissions for variant NM_001330260.2(SCN8A):c.718A>G (p.Ile240Val)

dbSNP: rs1064793923

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482488	SCV000567463	likely pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing	The I240V variant in the SCN8A gene has been previously published in association with seizures (McNally et al., 2016). This variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I240V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret I240V as a likely pathogenic variant.
Baylor Genetics	RCV001330496	SCV001522185	likely pathogenic	Cognitive impairment with or without cerebellar ataxia	2020-02-12	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001856835	SCV002242909	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the SCN8A protein (p.Ile240Val). 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 (PMID: 27659738; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419568). 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. This variant disrupts the p.Ile240 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been observed in individuals with SCN8A-related conditions (PMID: 31618753), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.