ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

SCN1B encodes the beta-1 subunit of a voltage gated sodium channel responsible for generating the action potential in excitable cells. Pathogenic variants in SCN1B have been associated with a variety of phenotype, including familial atrial fibrillation, Brugada Syndrome, cardiac conduction defects, generalized epilepsy with febrile seizures plus, and Early infantile epileptic encephalopathy (OMIM 600235). In the literature, there is a lack of clinical manifestations in carrier parents of children with the autosomal recessive condition, Dravet syndrome, even when the causative variant potentially leads to loss of function. Ramadan et al. 2017 (PMID 28218389) identified a homozygous splicing variant located at the beginning of exon 4 in a patient with severe developmental epileptic encephalopathy. Patino et al. 2009 (PMID 19710327) discovered a homozygous missense mutation that had little to no cell surface expression. Parents were clinically unaffected in both cases. However, there have been cases reported of heterozygous, potentially LOF mutations associated with epilepsy. Butler et al. 2017 (PMID 29056246) discovered a pathogenic frameshift in exon 3 leading to a premature stop codon in a patient with hypotonia and seizures. The authors also found a likely pathogenic frameshift leading to a premature stop codon in a patient with developmental delay, seizures with an abnormal EEG, and high myopia. Unfortunately information about parents was not available for these cases. Of note, cardiac disease associated with mutations in SCN1B seem to primarily be caused by missense variants.

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

Triplosensitivity phenotype comment:

? Heide et al. 2017 (PMID 28284480) reported a 1.45 Mb de novo duplication of 6 genes including SCN1B. The patient had an isolated corpus callosum abnormality. The five other genes included in the duplication were HAMP, COX6B1, PSENEN, NPHS1, and TYROBP. The HAMP gene encodes hepcidin, which plays a role in iron absorption. COX6B1 encodes a subunit of cytochrome c oxidase (COX), which plays a role in the electron transport chain. PSENEN encodes a subunit of the presenilin enhancer 2, which is important in the Notch signaling pathway. NPHS1 encodes nephrin, primarily found in the kidneys' filtration barrier. TYROBP encodes a tyrosine kinase binding protein. SCN1B was the only gene considered by the authors to be a candidate gene for the patient's phenotype based on the high expression of SCN1B to the brain and its role as a propagator of action potentials.