ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1147C>G (p.Gln383Glu) (rs796053178)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189204 SCV000242836 pathogenic not provided 2013-03-14 criteria provided, single submitter clinical testing p.Gln383Glu (CAA>GAA): c.1147 C>G in exon 9 of the SCN2A gene (NM_021007.2). The Gln383Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as an uncharged Glutamine residue is replaced by a negatively charged Glutamic acid residue. Gln383Glu alters a conserved position between the S5 and S6 segments of the first transmembrane domain of the protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Invitae RCV000549343 SCV000639611 pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2017-06-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 383 of the SCN2A protein (p.Gln383Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (rs796053178, ExAC no frequency). This variant has been reported in the literature in an individual with Ohtahara syndrome and a sibling affected with benign familial neonatal-infantile seizures inherited from an obligate carrier father affected with infantile epilepsy and intellectual disability (PMID: 27781028). In addition, family studies have indicated that this variant was not present in the parents of an individual with early-onset epilepsy, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 207050). 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"). For these reasons, this variant has been classified as Pathogenic.

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