Holt-Oram syndrome: genes and variants
Holt-Oram syndrome is linked to 1 analyzed protein (TBX5). 13 DNA variants are known to cause it; 26 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Holt-Oram syndrome
TBX5: T-box transcription factor TBX5
It directs upper-limb and cardiac developmental programs and later helps maintain cardiac conduction gene expression. Haploinsufficiency causes Holt-Oram syndrome, characterized by radial-ray limb abnormalities and congenital heart or conduction defects.
13 disease-causing and 26 uncertain variants in TBX5 are linked to Holt-Oram syndrome.
Where Holt-Oram syndrome variants cluster
- TBX5 T-box (positions 58–238): 9 of 13 disease-causing changes, 2.0× more than its size predicts.
Known disease-causing variants in Holt-Oram syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| TBX5 T223M | 223 | T-box | Disease-causing (★★) |
| TBX5 F232L | 232 | T-box | Disease-causing (★) |
| TBX5 G235E | 235 | T-box | Disease-causing (★) |
| TBX5 D118G | 118 | T-box | Disease-causing (★) |
| TBX5 W121L | 121 | T-box | Disease-causing (★) |
| TBX5 P132T | 132 | T-box | Disease-causing (★) |
| TBX5 I54T | 54 | Disease-causing | |
| TBX5 G80R | 80 | T-box | Disease-causing |
| TBX5 P85S | 85 | T-box | Disease-causing |
| TBX5 K226R | 226 | T-box | Disease-causing |
| TBX5 P35S | 35 | Disease-causing | |
| TBX5 Q49K | 49 | Disease-causing | |
| TBX5 S282F | 282 | Disease-causing |
Which prediction tools work for Holt-Oram syndrome
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 66 out of 100
Same protein, different disease
- Aortic valve disease 2 is also caused by TBX5 variants; they fall partly in the same places as the Holt-Oram syndrome variants (9 disease-causing).
Diseases related to Holt-Oram syndrome
- Aortic valve disease 2, also linked to TBX5
- Familial atrioventricular septal defect, also linked to TBX5
Frequently asked questions
Which genes are linked to Holt-Oram syndrome?
In CATVariant, Holt-Oram syndrome is linked to 1 analyzed protein: TBX5 (T-box transcription factor TBX5).
How many genetic variants are linked to Holt-Oram syndrome?
74 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 26 are of uncertain significance or have conflicting reports.
Which uncertain variants in Holt-Oram syndrome look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
Which variant effect predictor works best for Holt-Oram syndrome?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.66, based on 10 disease-causing and 24 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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