Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000432281 | SCV000524405 | likely pathogenic | not provided | 2017-07-17 | criteria provided, single submitter | clinical testing | A W1594C variant that is likely pathogenic has been identified in the SCN2A gene. A different nucleotide substitution (c.4782 G>T) resulting in the same amino acid change, W1594C, has been reported previously as a de novo variant in an individual with neonatal seizures, intellectual disability, and polymicrogyria; this individual also had a de novo variant in the RAI1 gene (Poirier et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1594C 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. This substitution occurs at a conserved position predicted to be within transmembrane segment S3 in the fourth homologous domain of the SCN2A protein, and missense variants in nearby residues (G1593R, D1598G) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Ambry Genetics | RCV002318437 | SCV000851323 | uncertain significance | Inborn genetic diseases | 2016-11-01 | criteria provided, single submitter | clinical testing | The p.W1594C variant (also known as c.4782G>C), located in coding exon 25 of the SCN2A gene, results from a G to C substitution at nucleotide position 4782. The tryptophan at codon 1594 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study which performed exome sequencing on individuals with cortical malformations, this alteration was detected as a de novo occurrence in an individual with neonatal seizures and perisylvian polymicrogyria who also carried the de novo RAI1 p.L855P alteration. It is unclear whether this individual's epilepsy phenotype is due to their genotype or their cortical malformation (Poirier K et al. Nat. Genet., 2013 Jun;45:639-47).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |