ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 12q24.21
  • GRCh37/hg19 chr12: 115,108,059-115,121,969
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr12: 114,670,255-114,684,175
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12668170 Wollnik et al. (2002) reported a frameshift pathogenic variant (TBX3: c.88_89insA , M30fsX110) segregation among 10 family members spanning 3 generations in a large Turkish family affected with ulnar-mammary syndrome. The phenotypic expression of the disease was highly variable among the affected family members.
28145909 Tanteles et al. (2017) identified a heterozygous pathogenic variant (TBX3: c.1423C>T, p.Glu475Ter) in a Cypriot family in which twin brothers and their father had ulnar-mammary syndrome. The variant segregated with the disorder in the family. The twins showed classic features of the disorder, whereas their father was mildly affected.
12116211 Sasaki et al. (2002) identified a heterozygous pathogenic variant (TBX3: TBX3: c.817A>T, p.Lys273Ter) in a Japanese mother and her 2 sons with ulnar-mammary syndrome, micropenis with or without cryptorchidism, and hypoplastic nipples in the brothers; and hypoplastic mammary glands and nipples, poor perspiration, and bicornuate uterus in the mother.

Haploinsufficiency phenotype comments:

Haploinsufficiency of TBX3 has been associated with ulnar-mammary syndrome (UMS), an autosomal dominant pleotropic disorder characterized with mammary and apocrine gland hypoplasia, upper limb defects, malformations of areola, dental structures, heart and genitalia. Variable expressivity has been well-documented for this syndrome. Additional Evidence: Khan et al, 2020 (PMID:31669645) summarized total eighteen UMS causing pathogenic variants of TBX3 gene including 5 nonsense, 8 frameshift (due to deletion and insertion), 3 missense and 2 splice site mutations. Among all of these, fifteen variants present apparently haploinsufficiency.

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

Triplosensitivity phenotype comment:

Although somatic PBX3 overexpression has been associated with tumor formation, angiogenesis and metastasis in several cancer type including breast cancer, colorectal cancer, etc. due to its tumor suppressor role. Currently there is no available evidence for TBX3 triplosensitivity in the hereditary disease.