Submissions for variant NM_001330260.2(SCN8A):c.457A>C (p.Asn153His)

gnomAD frequency: 0.00001  dbSNP: rs796053232

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189297	SCV000242930	uncertain significance	not provided	2017-10-23	criteria provided, single submitter	clinical testing	p.Asn153His (AAC>CAC): c.457 A>C in exon 4 of the SCN8A gene (NM_014191.3). A variant of unknown significance has been identified in the SCN8A gene. The N153H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,200 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 alters a highly conserved position predicted to be within the extracellular loop between the S1 and S2 transmembrane segments of the first homologous domain. The N153H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Fulgent Genetics, Fulgent Genetics	RCV000763859	SCV000894793	uncertain significance	Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299725	SCV001488830	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 153 of the SCN8A protein (p.Asn153His). This variant is present in population databases (rs796053232, gnomAD 0.002%). 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: 207139). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.