ClinVar Miner

Submissions for variant NM_014191.4(SCN8A):c.5614C>T (p.Arg1872Trp) (rs796053228)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189289 SCV000242921 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The R1872W variant in the SCN8A gene has been reported previously as a de novo variant in a patient with early-onset epileptic encephalopathy (Ohba et al., 2014). The R1872W variant is not observed in large population cohorts (Lek et al., 2016). The R1872W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies showed R1872W impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity (Wagnon et al., 2016). Missense variants at the same residue (R1872L, R1872Q) have been reported in the Human Gene Mutation Database in association with SCN8A-related disorder (Stenson et al., 2014), supporting the functional importance of this residue. We interpret R1872W as a pathogenic variant.
GeneReviews RCV000239726 SCV000298215 pathogenic Early infantile epileptic encephalopathy 13 2016-02-19 no assertion criteria provided literature only
Invitae RCV000229600 SCV000289942 pathogenic Early infantile epileptic encephalopathy 2016-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1872 of the SCN8A protein (p.Arg1872Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with early-onset epileptic encephalopathy (PMID: 24888894, 25951352, 25568300). ClinVar contains an entry for this variant (Variation ID: 207131). Additional amino acid substitutions at this codon have also been reported in individuals affected with early-onset epileptic encephalopathy (PMID: 26029160, 25568300). This codon is located in the C-terminal cytoplasmic domain and it has been suggested that changes at this codon affect the ability of the SCN8A protein to interact correctly with accessory proteins (PMID: 24888894) For these reasons, this variant has been classified as Pathogenic.
Neurogenetics Laboratory - MEYER,AOU Meyer RCV000416947 SCV000494531 pathogenic Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing

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