ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.