ClinVar Genomic variation as it relates to human health

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.

This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 28379373, 29100083, 30619928, 31054490). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207019). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1629 of the SCN2A protein (p.Arg1629His).

The c.4886G>A (p.Arg1629His) missense variant in SCN2A gene has been reported 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 (Sandu et al., 2017). The p.Arg1629His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 1629 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic/Uncertain Significance. The amino acid change p.Arg1629His in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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 (Nakamura et al., 2013; Nashabat et al., 2019). For these reasons, this variant has been classified as Likely Pathogenic.

The c.4886G>A (p.R1629H) alteration is located in exon 27 (coding exon 26) of the SCN2A gene. This alteration results from a G to A substitution at nucleotide position 4886, causing the arginine (R) at amino acid position 1629 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple unrelated patients with epilepsy (Hamdan, 2017; Wolff, 2017; Kong, 2019). In addition, two other alterations affecting the same amino acid, p.R1629P and p.R1629L, were reported in patients with epilepsy (Nakamura, 2013; Symonds, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-07-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight and, in one family in multiple siblings. Additional phenotypic information for other sibling(s) might be available from Simons Searchlight.