ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-30692
• Date last evaluated: 2020-09-23
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/6926
• OMIM: https://omim.org/entry/601621

Location Information

• 12q24.21
• GRCh37/hg19 chr12: 115,108,059-115,121,969

Evidence for Loss Phenotypes

• Loss of function score: 3
• Strength of Evidence: Sufficient evidence for dosage pathogenicity
• Haploinsufficiency phenotype: ULNAR-MAMMARY SYNDROME; UMS

Evidence for loss of function 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.

• Loss of function 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.

Evidence for Triplosenstive Phenotype

• Triplosensitivity score: 0
• Strength of Evidence: 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.

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.