ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

In addition, missense changes in SCN2A have been associated with benign familial infantile seizures (607745). After reviewing genetic testing results of 71 unpublished patients and 130 published cases, Wolff M, et al (28379373) suggested that there are two distinct groups of SCN2A variants. One group contains missense variants with gain-of-function and associated with early infantile epilepsy with onset before 3 months of age. The other group frequently contains loss-of-function variants (truncations and splice site variants, and missense mutations with loss-of-function effects), and associated with later onset epilepsy, intellectual disability and/or autism without epilepsy.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Simonetti et al PMID: 23016767 review 2q24 duplications in patients with early onset epilepsy (3 patients in this study, along with patients from other studies). None of the reported duplications include only the SCN2A gene.