ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
32917966 Meng Y et al. (2020) performed targeted exome sequencing of 4800 genes in 347 Chinese patients with a clinically suspected diagnosis of tuberous sclerosis. Among the nonsynonymous variants detected, there were 51 TSC1 variants identified that were classified based on ACMG guidelines as either pathogenic, likely pathogenic, or variants of uncertain significance. Of these TSC1 variants, 37 were nonsense, frameshift, or canonical splice site.
23389244 Niida Y et al. (2013) sequenced the coding regions of TSC1 and TSC2 in 57 Japanese patients with tuberous sclerosis (46 with a definite and 11 with a suspected diagnosis). Eleven TSC1 variants were identified, including 1 missense variant, 9 loss-of-function (frameshift, nonsense, and canonical splice site) variants, and 1 large deletion of exons 17-19 (by long PCR).
17304050 Au KS et al. (2007) sequenced all the coding regions of TSC1 and TSC2 in 368 patients in the United States with a clinical diagnosis of tuberous sclerosis. Among these patients, 61 TSC1 variants were identified. Of these 61 variants, 21 were nonsense variants. Another 39 were deletion, insertion, splice alternative, or splice deletion variants, but it was not indicated if these would cause a frameshift or loss of canonical splice site.

Haploinsufficiency phenotype comments:

Although the evidence presented here is specific to the tuberous sclerosis phenotype, variants in TSC1 have also been observed in individuals with isolated lymphangioleiomyomatosis (OMIM #606690). Somatic variants in TSC1 have been observed in individuals with focal cortical dysplasia, type II (OMIM #607341). Of note, both of these are features of tuberous sclerosis (PMID 20301399).

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