ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
31525612 Published in 2019, Lin et al. used Sanger sequencing and Multiplex ligation-dependent probe amplification (MLPA) on 77 unrelated Chinese individuals diagnosed with Tuberous sclerosis complex to assess variants in TSC1 and TSC2. This study found 3 nonsense variants, 6 splicing variants, a total of 18 frameshift variants, and 2 large deletions in TSC2. Additionally, 51.9% of the cohort (39 individuals) had de novo variants in TSC2.
10205261 Published in 1999, Jones et al. used PCR and single-strand confirmation polymorphism (SSCP) and Heteroduplex analysis on 150 Tuberous sclerosis complex patients and their families to assess variants in TSC1 and TSC2. The methodology found that 9 cases of variants in TSC2 were familial; 88 other cases involving TSC2 variants were sporadic. This study identified 20 nonsense variants, 21 small insertions or deletions, 8 splice variants, 5 in-frame deletions, and 8 large intragenic deletions in TSC2.
29932062 Published in 2014, Glushkova et al. used Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) on 17 unrelated individuals who met the clinical description for Tuberous sclerosis complex (TSC) to search for variants in TSC1 and TSC2. This study identified 2 nonsense variants, 3 frame-shift variants, 1 splice variant, and 1 large deletion in TSC2. In terms of inheritance, 4 individuals had a de novo variant.

Haploinsufficiency phenotype comments:

Variants involving the TSC2 gene, including intragenic and whole-gene heterozygous deletions, cause tuberous sclerosis complex (TSC). TSC is an autosomal dominant multi-system disorder, which affects 1 in 6000 people. About half of these patients are affected by intellectual disability. PMID 11030407: Reviewed 222 TSC2 mutations that had been reported in the literature. Large genomic deletions (intragenic and whole-gene) accounted for 16% of all variants reported. Larger heterozygous deletions, involving the TSC2 and adjacent PKD1 gene, result in the TSC2/PKD1 contiguous gene syndrome (PKDTS) [PMIDs 22169896, 18818683, 14695542, 17185137). PKDTS has been identified in patients with tuberous sclerosis complex (TSC) and early-onset severe autosomal dominant polycystic kidney disease (ADPKD).

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

Triplosensitivity phenotype comment:

No literature identified