TBX5

protein-coding

T-box transcription factor 5, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_181486.4

Inheritance

ClinVar variants

P:201U:298B:216

Top phenotype

Holt-Oram syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr12:114,353,911-114,408,442

External References & Databases

Ensembl (ENSG00000089225)

Transcript & Mutation Effects

hg38 • Region Span ~54.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Holt-Oram syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: ClinGen

The T-box 5 (TBX5) gene is located on chromosome 12 at 12q24.21 and encodes a transcriptional regulator that is involved in cardiac development and limb pattern formation Mutations in TBX5 were first reported in relation to autosomal dominant Holt-Oram syndrome (HOS), a developmental disorder affecting the heart and upper limb, in 1997 (Basson et al., 1997, PMID: 8988165; Li et al., 1997, PMID: 8988164). At least 120 unique variants (missense, nonsense, frameshift, small deletions) have been reported in humans, the majority which are de novo. The upper-limb malformations associated with HOS are fully penetrant, whereas the congenital heart malformations associated with the disease may be less so. In some cases, the cardiac phenotype may be recognized prior to limb anomalies, as some upper limb malformations have a very mild presentation. In patients with mild upper limb anomalies, conduction defects may present well into adulthood with reverse phenotyping prompting skeletal assessment (PMID 29755943). Cardiac conduction defects that are associated with HOS may occur in the presence or absence of structural heart defects. While septal defects are the most common structural disease association, cardiac phenotypes including dilated and non-compaction cardiomyopathies, and complex congenital heart diseases including dextrocardia, tetralogy of fallot, and double outlet right ventricle have been reported (PMIDs 3055242, 25344219, 32449309). Evidence supporting this gene-disease relationship includes case-level and experimental data.The mechanism for TBX5 is haploinsufficiency (Basson et al., 1999, PMID:10077612; Gruenauer-Kloevekorn et al., 2003, PMID 12818525; Baban et al., 2014, PMID 24664498). This gene-disease association is supported by animal models, protein interaction studies. Functional alterations were also shown in non-patient cells harbouring missense variants in TBX5 in different affected individuals. In summary, TBX5 is definitively associated with Holt-Oram syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 26Jan2021 (SOP Version 8). The summary was updated by the ClinGen Hereditary Cardiovascular Disease GCEP after meeting on March 25, 2025.

Holt-Oram syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: Orphanet

Holt-Oram syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: PanelApp Australia

heart conduction diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000992

Submitter: Genomics England PanelApp

Holt-Oram syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: G2P

Holt-Oram syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: Ambry Genetics

Holt-Oram syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007732

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Holt-Oram syndromeAD

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: While the condition may be recognizable in the majority, individuals may have cardiac conduction abnormalities even without known cardiac malformations, and surveillance (eg, with electrocardiography) may allow early detection and management

Refs: 14402857; 8730285; 8911604; 8988165; 8988164; 10077612; 10842287; 12818525; 17366586; 18818409; 20301290

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX5 variants in ClinVar

22 Conditions Cataloged

Cardiovascular phenotypeTotal: 400

Aortic valve disease 2Total: 371

Holt-Oram syndromeTotal: 152

not providedTotal: 131

TBX5-related disorderTotal: 29

not specifiedTotal: 24

Abnormal heart morphologyTotal: 2

Primary dilated cardiomyopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181486.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	3 clinvar	170 clinvar	5 clinvar	180
missense	16 clinvar	24 clinvar	288 clinvar	41 clinvar		369
nonsense	44 clinvar	7 clinvar	4 clinvar			55
start loss						0
frameshift	74 clinvar	8 clinvar	2 clinvar			84
splice donor/acceptor (+/-2bp)	15 clinvar	11 clinvar	1 clinvar			27
Total	150	51	298	211	5	715

Highest pathogenic variant AF is 0.0000065725476

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181486.4	RefSeq	NP_852259.1	8	MANE Select
ENST00000405440.7	Ensembl	ENSP00000384152.3	8	MANE Select
NM_000192.3	RefSeq	NP_000183.2	8	Standard
NM_080717.4	RefSeq	NP_542448.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbx5a	Danio rerio	Structure: cardiac muscle cell Quality: dissociated from abnormal

Gene / Model

Organism

Observed Phenotype

tbx5a

Danio rerio

Structure: cardiac muscle cell

Quality: dissociated from

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Heart Development
Cardiac Progenitor Differentiation
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

morphogenesis of an epithelium
bundle of His development
atrioventricular valve morphogenesis
endocardial cushion development
cardiac left ventricle formation

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
protein-containing complex
protein-DNA complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310346
Coding exons: 8
Length: 54512
Individuals with no LoFs: 125556
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125558
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	234	291	0.803	0.0000153	3423
Missense (PolyPhen)		49	81.032	0.6047		997
Synonymous	-3.44	170	122	1.40	0.00000717	1004
Loss of Function	4.35	0	22.1	0.00	0.00000103	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation (PubMed:25725155, PubMed:25963046, PubMed:29174768, PubMed:26917986, PubMed:27035640, PubMed:8988164). Binds to the core DNA motif of NPPA promoter (PubMed:26926761). {ECO:0000269|PubMed:25725155, ECO:0000269|PubMed:25963046, ECO:0000269|PubMed:26917986, ECO:0000269|PubMed:26926761, ECO:0000269|PubMed:27035640, ECO:0000269|PubMed:29174768, ECO:0000269|PubMed:8988164}.;
Disease: DISEASE: Holt-Oram syndrome (HOS) [MIM:142900]: Developmental disorder affecting the heart and upper limbs. It is characterized by thumb anomaly and atrial septal defects. {ECO:0000269|PubMed:10077612, ECO:0000269|PubMed:10842287, ECO:0000269|PubMed:12818525, ECO:0000269|PubMed:15735645, ECO:0000269|PubMed:20450920, ECO:0000269|PubMed:8988164, ECO:0000269|PubMed:8988165}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in TBX5 are associated with susceptibility to heart disorders including dilated cardiomyopathy (DCM) and atrial fibrillation (AF). DCM is characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death. AF is a common sustained cardiac rhythm disturbance. AF is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:25725155, ECO:0000269|PubMed:25963046, ECO:0000269|PubMed:26917986, ECO:0000269|PubMed:27035640}.;

Recessive Scores

pRec: 0.209

Intolerance Scores

RVIS EVS: -0.55
RVIS percentile EVS: 19.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.937

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium