TBX5

Chr 12AD

T-box transcription factor 5

Also known as: HOS

NCBI Gene: 6910ENSG00000089225UniProt: Q99593

The protein functions as a transcription factor that regulates gene expression during heart development and limb pattern formation. Mutations cause Holt-Oram syndrome through an autosomal dominant inheritance pattern, a developmental disorder affecting the heart and upper limbs. The pathogenic mechanism involves loss of function of this essential developmental regulator.

Summary from RefSeq, OMIM, UniProt, Mechanism

Primary Disease Associations & Inheritance

Holt-Oram syndromeMIM #142900
AD
0
Active trials
56
Pubs (1 yr)
53
P/LP submissions
10%
P/LP missense
0.14
LOEUF· LoF intol.
LOF
Mechanism· G2P
Clinical Summary— TBX5
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Gene-Disease Validity (ClinGen)
Holt-Oram syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
49 unique Pathogenic / Likely Pathogenic· 218 VUS of 400 total submissions
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GeneReview available — TBX5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.14LOEUF
pLI 1.000
Z-score 4.35
OE 0.00 (0.00–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
1.19Z-score
OE missense 0.80 (0.72–0.90)
234 obs / 291.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.00 (0.00–0.14)
0≤0.351.4
Missense OE0.80 (0.72–0.90)
0≤0.61.4
Synonymous OE1.40
0≤1.21.6
LoF obs/exp: 0 / 22.1Missense obs/exp: 234 / 291.4Syn Z: -3.44
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTBX5-related Holt-Oram syndromeLOFAD
DN
0.3495th %ile
GOF
0.2995th %ile
LOF
0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 61% of P/LP variants are LoF · LOEUF 0.14
GOF1 literature citation

Literature Evidence

GOFA gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillationPMID:18451335
LOFModeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.PMID:33321106

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic11
VUS218
Likely Benign125
Benign1
Conflicting5
38
Pathogenic
11
Likely Pathogenic
218
VUS
125
Likely Benign
1
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
2
11
0
38
Likely Pathogenic
5
3
3
0
11
VUS
1
200
17
0
218
Likely Benign
0
6
22
97
125
Benign
0
0
0
1
1
Conflicting
—5
Total312115398398

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TBX5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients