Submissions for variant NM_001330260.2(SCN8A):c.3943G>T (p.Val1315Leu)

dbSNP: rs1555228303

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498624	SCV000590727	likely pathogenic	not provided	2017-06-23	criteria provided, single submitter	clinical testing	A novel c.3943 G>T variant that is likely pathogenic has been identified in the SCN8A gene. The c.3943 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3943 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.3943 G>T may damage the natural splice acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.3943 G>T does not alter splicing, it will result in the V1315L missense change, which is a conservative amino acid substitution. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense substitution at the same position (V1315M) has been reported previously as a de novo change in an individual with early infantile epileptic encephalopathy (Trump et al., 2016). Therefore, the V1315L variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865573	SCV002252757	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-12-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1315 of the SCN8A protein (p.Val1315Leu). 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: 29432985; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Val1315 amino acid residue in SCN8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26993267, 29432985, 31026061). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.