ClinVar Miner

Submissions for variant NM_001330260.2(SCN8A):c.2983A>G (p.Asn995Asp)

dbSNP: rs1565917769
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000698952 SCV000827643 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 995 of the SCN8A protein (p.Asn995Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN8A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
New York Genome Center RCV001542340 SCV001761028 likely pathogenic Developmental and epileptic encephalopathy, 13 2020-05-21 criteria provided, single submitter clinical testing The de novo c.2983A>G (p.Asn995Asp) variant identified in the SCN8A gene substitutes a fully conserved Asparagine for Aspartic Acid at amino acid 995/1981 (coding exon 17/27). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms predict this variant to be Deleterious (Provean; score: -4.78) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:576451) and to our current knowledge has not been reported in affected individuals in the literature. The p.Asn995 residue is within the second transmembrane domain of SCN8A (UniProtKB:Q9UQD0), where other pathogenic variants have been reported in affected individuals (for Review [PMID:26029160]). Given its presence de novo in the affected individual, its absence in population databases, and prediction of damaging effect on the canonical transcript, the c.2983A>G (p.Asn995Asp) variant identified in the SCN8A gene is reported here as Likely Pathogenic.

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