GeneBe

TBX20

protein-coding

T-box transcription factor 20, the group of T-box transcription factors

Gene summary

This gene encodes a T-box family member. The T-box family members share a common DNA binding domain, termed the T-box, and they are transcription factors involved in the regulation of developmental processes. This gene is essential for heart development. Mutations in this gene are associated with diverse cardiac pathologies, including defects in septation, valvulogenesis and cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

MANE transcript

NM_001077653.2

Inheritance

AD

ClinVar variants

P:48U:403B:174

Top phenotype

Atrial septal defect 4

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr7:35,202,430-35,254,100

External References & Databases

Ensembl (ENSG00000164532)NCBI Gene (57057)OMIM (606061)HGNC:11598GenCCUniProt (Q9UMR3)AlphaFoldClinVar (TBX20)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

dilated cardiomyopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

TBX20 was originally evaluated for DCM by the ClinGen DCM GCEP on 8/12/20. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 2/5/2025. As a result, the classification did change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. TBX20 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2007 (Kirk et al, PMID: 17668378. Human genetic evidence supporting the gene-disease relationship with DCM includes case-level, case-control and segregation data. Multiple unique variants (missense and truncating) in TBX20 have been reported in individuals with DCM, Left Ventricular Non-Compaction (LNVC), Congenatal Heart Disease and/or Wolff-Parkinson-White Syndrome (Kirk et al, 2007, PMID: 17668378; Qian et al, 2008 PMID: 19074289; Amor-Salamanca et al 2024 PMID: 38353104; Chang et al 2024 PMID: 37657916), 6 of which were scored as variant evidence for this curation. One case-control study using aggregate variant analysis found that TBX20 truncating variants were enriched in probands with DCM/LVNC compared to internal and external control groups, with an odds ratio of 73.23 (p<0.0001; Amor-Salamanca et al 2024, PMID: 38353104). Segregation evidence from two studies, using candidate gene or genome-wide sequencing, showed that TBX20 truncating variants segregated with DCM/LNVC phenotypes, with a combined LOD score of 5.73 (Amor-Salamanca et al 2024 PMID: 38353104; Chang et al 2024 PMID: 37657916). Additional publications that presented genetic evidence were excluded due to concerns of suspect data (Zhao et al, 2016, PMID: 26118961; Zhou et al, 2016, PMID:27510170). In addition, this gene-disease association is supported by animal models and expression studies. The mechanism of disease is unclear at this time as TBX20 loss-of-function and gain-of-function (overexpression) animal models have produced similar phenotypes (Stennard et al, 2005,PMID: 15843414, Zhang et al, 2011, PMID: 21890625). In summary, TBX20 is strongly associated with AD DCM. Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional experimental evidence to accumulate before upgrading to a final Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 2nd, 2025 (SOP Version 10).

congenital heart diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

TBX20 was first reported in relation to autosomal dominant congenital heart disease in 2007 (Kirk et al.; PMID: 17668378). Fifteen variants (promoter region, missense, nonsense) that have been reported in fifteen probands in eleven publications (PMIDs: 17668378, 19762328, 18834961, 25183037, 25625280, 27510170, 28553164, 30820038, 37481008, 39402625, 40075846) are included in this curation. The maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss-of-function (PMIDs: 25625280, 30820038, 39402625, 40075846). This gene-disease relationship is also supported by animal models and protein interaction experimental evidence with GATA4 and NKX2-5, which are two genes that have been definitively associated with congenital heart disease (PMIDs: 14550786, 15843414,19494035, 22328084). This gene-disease pair was originally evaluated by the Congenital Heart Disease GCEP on 5/7/2024 (SOP Version 10). It was reevaluated on 7/7/2026 (SOP Version 12). As a result of this reevaluation, the classification increased from moderate to definitive with the addition of genetic evidence (PMIDs: 22465533, 25625280, 30820038, 39402625, 40075846). This gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

atrial septal defect 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012654

Submitter: PanelApp Australia

atrial septal defect 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012654

Submitter: Ambry Genetics

atrial septal defect 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012654

Submitter: Labcorp Genetics (formerly Invitae)

atrial septal defect 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012654

Submitter: G2P

Clinical Genomic Database (CGD)

Atrial septal defect 4AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Variants can result in a wide spectrum of cardiac-related disease, some of which may be challenging to recognize, and awareness may allow early medical and/or surgical management of manifestations, which can include valvular disease and cardiomyopathy in addition to frank structural anomalies such as ASD

Refs: 17668378; 19762328Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX20 variants in ClinVar

12 Conditions Cataloged
not providedTotal: 592
Cardiovascular phenotypeTotal: 309
Atrial septal defect 4Total: 39
TBX20-related disorderTotal: 16
not specifiedTotal: 8
Primary dilated cardiomyopathyTotal: 6
Aortic valve disease 1Total: 4
Wolff-Parkinson-White patternTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001077653.2. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
164
clinvar
1
clinvar
 169
missense
1
clinvar
2
clinvar
380
clinvar
9
clinvar
 392
nonsense
11
clinvar
5
clinvar
5
clinvar
 21
start loss
1
clinvar
 1
frameshift
19
clinvar
1
clinvar
10
clinvar
 30
splice donor/acceptor (+/-2bp)
9
clinvar
3
clinvar
 12
Total31174031731625

Highest pathogenic variant AF is 0.0000065749678

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001077653.2RefSeqNP_001071121.18MANE Select
ENST00000408931.4EnsemblENSP00000386170.38MANE Select
NM_001166220.1RefSeqNP_001159692.16Standard
XM_017012456.2RefSeqXP_016867945.15Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tbx20Danio rerio

Structure: cardiac muscle cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Heart Development
  • Cardiac Progenitor Differentiation

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • branching involved in blood vessel morphogenesis
  • endoderm formation
  • neuron migration
  • heart looping

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • RNA polymerase II transcription factor binding
  • RNA polymerase II activating transcription factor binding

Cellular Component

  • nucleus
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000408931
Coding exons
8
Length
51717
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125743
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.681762510.7010.00001252908
Missense (PolyPhen)4485.70.51342989
Synonymous-0.6041091011.080.00000512908
Loss of Function3.72220.00.1000.00000109218

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000270.000026rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart. {ECO:0000250}.;
Disease
DISEASE: Atrial septal defect 4 (ASD4) [MIM:611363]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Patients show other heart abnormalities including defects in septation, chamber growth and valvulogenesis. The disease is not associated with defects in the cardiac conduction system or with non-cardiac abnormalities. {ECO:0000269|PubMed:17668378, ECO:0000269|PubMed:19762328}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.147

Intolerance Scores

LoFtool
0.130
RVIS EVS
-0.78
RVIS percentile EVS
12.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.981

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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