ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.4886G>A (p.Arg1629His) (rs796053157)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189171 SCV000242803 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R1629H variant in the SCN2A gene has been reported previously as a de novo variant in an individual with neonatal seizures and severe intellectual disability (Wolff et al., 2017). The variant has also been reported in a child with neonatal onset of multifocal seizures and developmental delay, and itwas inherited from this individual's mother who had a history of neonatal seizures (Sandu et al., 2017). The R1629H variant has also been identified at GeneDx as a de novo variant in two unrelatedindividuals with epilepsy. The R1629H variant is not observed in large population cohorts (Lek et al., 2016). The R1629H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. In-silicoanalyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN2A-related disorders (Stenson et al., 2014; Nakamura et al., 2013). Therefore, we interpret R1629H as a pathogenic variant and its presence is consistent with thediagnosis of an SCN2A-related disorder in this individual.
Invitae RCV000536734 SCV000639633 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2017-04-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1629 of the SCN2A protein (p.Arg1629His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 207019). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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