ClinVar Miner

Submissions for variant NM_014191.4(SCN8A):c.5630A>G (p.Asn1877Ser) (rs587780455)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118288 SCV000152660 uncertain significance not provided 2013-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000118288 SCV000242923 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The N1877S variant has been reported multiple families with focal and generalized seizures with and without developmental delay present (Anand et al., 2016; Butler et al., 2017). Additionally, the N1877S variant has been identified as a de novo change in multiple unrelated individuals with epilepsy previously tested at GeneDx. The N1877S variant is not observed in large population cohorts (Lek et al., 2016). The N1877S variant is a conservative amino acid substitution. This substitution is predicted to be within the C-terminal cytoplasmic domain of the protein, and missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN8A-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000118288 SCV000338930 uncertain significance not provided 2016-01-12 criteria provided, single submitter clinical testing
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000416967 SCV000494532 likely pathogenic Focal epilepsy 2016-11-16 criteria provided, single submitter clinical testing
Invitae RCV000467598 SCV000544808 pathogenic Early infantile epileptic encephalopathy 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1877 of the SCN8A protein (p.Asn1877Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with early onset focal epileptic seizures without cognitive or neurological impairment (PMID: 27210545). This variant has been shown to be de novo in an individual affected with epilepsy (Invitae). This variant has also been shown to segregate with disease in a family affected with epilepsy (Invitae). ClinVar contains an entry for this variant (Variation ID: 130252). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000239702 SCV000297996 pathogenic Seizures, benign familial infantile, 5 2016-08-22 no assertion criteria provided literature only
OMIM RCV000239630 SCV000297997 pathogenic Early infantile epileptic encephalopathy 13 2016-08-22 no assertion criteria provided literature only

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