ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.4782G>C (p.Trp1594Cys) (rs1057521747)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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 RCV000720446 SCV000851323 uncertain significance History of neurodevelopmental disorder 2016-11-01 criteria provided, single submitter clinical testing Insufficient evidence

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