Submissions for variant NM_001330260.2(SCN8A):c.5583G>C (p.Glu1861Asp)

gnomAD frequency: 0.00001  dbSNP: rs1352614116

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001565099	SCV001788375	uncertain significance	not provided	2024-12-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the C-terminal cytoplasmic domain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865997	SCV002152979	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2024-05-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1861 of the SCN8A protein (p.Glu1861Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200168). 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 not expected to disrupt SCN8A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003326154	SCV004032316	uncertain significance	Seizures, benign familial infantile, 5	2023-08-14	criteria provided, single submitter	clinical testing	Criteria applied: PP2
PreventionGenetics, part of Exact Sciences	RCV004536192	SCV004726790	uncertain significance	SCN8A-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The SCN8A c.5583G>C variant is predicted to result in the amino acid substitution p.Glu1861Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.