ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.2620G>T (p.Ala874Ser)

dbSNP: rs1057524820
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425333 SCV000536541 likely pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing The A874S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A874S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It has been identified as a confirmed de novo variant at GeneDx. The A874S variant is a non-conservative amino acid substitution that alters a conserved position predicted to be within the intracellular loop between the S4 and S5 transmembrane segments of the second homologous domain. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253698 SCV001429545 likely pathogenic Developmental and epileptic encephalopathy, 13 2017-05-10 criteria provided, single submitter clinical testing
Invitae RCV001315470 SCV001506045 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2020-04-01 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. 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"). This variant has not been reported in the literature in individuals with SCN8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 393169). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 874 of the SCN8A protein (p.Ala874Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine.

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