ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 12q24.21
  • GRCh37/hg19 chr12: 114,791,735-114,846,247
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr12: 114,353,911-114,408,708
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24664498 In 2014, Baban et al. used PCR on an individual with Holt-Oram syndrome to investigate TBX5. Analysis identified a confirmed de novo nonsense variant (p.Arg279Ter) in the proband. Per the authors, ?In accord with this data, Western blot analysis performed with two different antibodies against both the amino-terminal and the carboxyl end of TBX5, revealed the complete absence of the shorter isoform of the TBX5 protein (Fig. 1C). These data indicate that this mutant behaves as haploinsufficient allele (Table I).?
10077612 In 1999, Basson et al. used PCR on individuals with Holt-Oram syndrome to investigate TBX5. The authors identified 2 frameshift variants, 1 nonsense variant, and 1 splice site variant in affected individuals. These variants were confirmed as de novo. In the case of the nonsense variant, the variant was identified in a parent?s germline. Analysis also identified 3 other variants resulting in protein truncation which were familial, but the number of segregations in each case is not noted.
12818525 In 2003, Gruenauer-Kloevekorn et al. used PCR and direct sequencing on 2 unrelated families with Holt-Oram syndrome. Analysis identified the same nonsense variant (p.Y136X) resulting in protein truncation in both families. This variant was found in the proband of both families and a total of 4 affected family members across both families. This variant was not identified in unaffected individuals from either family.

Haploinsufficiency phenotype comments:

Mutations in TBX5 cause the autosomal dominant developmental disorder, Holt-Oram syndrome. Additional cases: PMID: 16917909 In 2006, Borozdin et al. used PCR and directing sequencing on 21 unrelated families with Holt-Oram syndrome to identify potential variants in TBX5 and SALL4. Analysis identified 9 variants in TBX5. Per the authors, ?seven mutations are truncating (3 nonsense mutations, 4 small deletions), and one splice donor site mutation is expected to result in exon skipping or activation of a cryptic splice site, and as such all mutations are predicted to cause the HOS phenotype via TBX5 haploinsufficiency.? There were 5 familial cases with a total of 6 segregations across the families, not including the probands, and 3 cases which appear to be de novo. PMID: 17534187 In 2007, Debeer et al. used PCR on 27 individuals with Holt-Oram syndrome to identify variants in TBX5. 7 patients had variants in TBX5. The authors identified 5 novel variants including 2 small deletions "(c.1128del1, c.726_730del5) resulting in the production of a truncated protein (Q376Q fs X393 and M242I fs X251, respectively), and a small duplication (K159_L160dup)."

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