Submissions for variant NM_001330260.2(SCN8A):c.71A>G (p.Asn24Ser)

gnomAD frequency: 0.00001  dbSNP: rs769269501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768310	SCV000898957	uncertain significance	Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5	2018-05-24	criteria provided, single submitter	clinical testing	SCN8A NM_014191.3 exon2 p.Asn24Ser (c.71A>G): This variant has not been reported in the literature and is present in 1/111162 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs769269501). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV002370026	SCV002668558	uncertain significance	Inborn genetic diseases	2019-01-31	criteria provided, single submitter	clinical testing	The p.N24S variant (also known as c.71A>G), located in coding exon 1 of the SCN8A gene, results from an A to G substitution at nucleotide position 71. The asparagine at codon 24 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224453	SCV003920454	uncertain significance	Cognitive impairment with or without cerebellar ataxia; Developmental and epileptic encephalopathy, 13; Seizures, benign familial infantile, 5; Myoclonus, familial, 2	2021-03-30	criteria provided, single submitter	clinical testing	SCN8A NM_014191.3 exon2 p.Asn24Ser (c.71A>G): This variant has not been reported in the literature and is present in 1/111162 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs769269501). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003753157	SCV004519658	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-12-11	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 626165). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is present in population databases (rs769269501, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 24 of the SCN8A protein (p.Asn24Ser).