ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
18781618 Screened 457 probands for mutations in TGFBR2 and found 23 mutations, including 3 nonsense variants.
15235604 Paper describes a loss-of-function splice mutation (synonymous but causes abnormal splicing) and a translocation disrupting TGFBR2 in Marfan type 2/Loeys-Dietz 2B. Another paper describes missense mutations and one nonsense mutation in patients with Marfan type 2/Loeys-Dietz 2B (PMID 16799921)
15731757 Paper by Loeys et al. describes a splice mutation that disrupts reading frame, causing loss of function-type alteration, removing amino acids. Another paper by Loeys lists various mutations including a loss-of-function splice mutation (PMID 16928994)

Haploinsufficiency phenotype comments:

Numberous heterozygous missense and nonsense mutations in TGFBR2 are linked to Loeys-Dietz syndrome (LDS) types 1B (MIM #610168) and 2B/Marfan (MIM #610380). The nonsense mutations are clustered in the C-terminus. The mechanism appears to be dominant negative rather than haploinsufficiency (PMID 21098638). One paper describes a 896-kb deletion including TGFBR2 but the patient had not signs of LDS but instead exhibited microcephaly and developmental delay (PMID 21567932). Due to the uncertainty regarding the exact mechanism by which mutations in TGFBR2 cause LDS, the haploinsufficiency rating is deemed a 2.

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