ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000008.10) (NC_000008.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20039262 A homozygous E210X variant was identified in four affected siblings with severe, progressive, childhood neuropathy. Parents are consanguineous and unaffected heterozygous carriers. Functional studies support loss of function.
19158810 Abe et al. 2009: Charcot-Marie-Tooth (CMT) patients were screened for mutations via multi-gene panel testing. Four heterozygous missense and one homozygous p.E140* variant were detected in NEFL among 223 CMT patients. The parents of this patient were unaffected carriers and consanguineous.

Haploinsufficiency phenotype comments:

Heterozygous missense variants in NEFL typically cause Charcot-Marie-Tooth types 2E and 1F. Most pathogenic variants are transcribed and produce a protein that is defective in neurofilament assembly and transport. There are a few reports of nonsense variants in NEFL associated with disease. In addition to the family described in PMID 19158810, a homozygous p.E210* variant was associated with severe, progressive neuropathy. This was attributed to biallelic NEFL loss of function (PMID:20039262). In another family, a heterozygous p.R421* variant showed evidence of producing a stable transcript. The authors hypothesized that the translated mutated protein interfered with normal functioning of the wild-type protein, causing disease in the family (PMID: 25264603). There is no evidence to suggest that haploinsufficiency of NEFL would carry an abnormal phenotype.

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

Triplosensitivity phenotype comment:

No evidence of triplosensitivity for the NEFL gene.