ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
22495306 Sanders et al. 2012 report WES data on probands from the Simons Simplex Collection (SSC) autism cohort. They found 279 de novo coding mutations, with 2 nonsense changes (G1013X and C959X) in SCN2A in the probands (not in the sibs). These individuals did not have a history of seizures.
15028761 Kamiya et al. 2004 analyzed SCN2A in 20 patients diagnosed with intractable childhood epilepsies. They found a de novo nonsense change (R102X) resulting in a truncated protein in a patient with delayed onset of early infantile epileptic encephalopathy-11 (613721). The seizures began at 1 year 7 months, and the patient was autistic.
28379373, 29655203 Wolff M, et al (2017) reported SCN2A variants in 34 patients with encephalopathy with late onset epilepsy (West syndrome, Lennox-Gastaut syndrome, myoclonicatonic epilepsy, and focal epilepsies with an ESES-like picture), intellectual disability and/or autism without epilepsy. There are 8 patients with de novo nonsense variants (all confirmed by Sanger sequencing). The rest are missense/splicing variants. Two selected de novo missense variants were confirmed to be loss-of-function variants by standard whole-cell patch clamp recording functional study. Lindy AS, et al (2018) reviewed the genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. They reported at least 4 truncating variants (nonsense or frame-shift, detected by NGS) of SCN2A. They reported that 90.2% of variants in SCN2A were de novo.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.