GeneBe

TNNT2

protein-coding

troponin T2, cardiac type, the group of Troponin complex subunits

Gene summary

This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

Previous symbols:
  • CMH2
  • CMD1D

MANE transcript

NM_001276345.2

Inheritance

AD, AR

ClinVar variants

P:109U:447B:170

Top phenotype

Cardiomyopathy, familial restrictive, 3; Cardiomyopathy, dilated, 1D; Left ventricular noncompaction 6; Cardiomyopathy, familial hypertrophic, 2

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr1:201,359,008-201,377,764

External References & Databases

Ensembl (ENSG00000118194)NCBI Gene (7139)OMIM (191045)HGNC:11949GenCCUniProt (P45379)AlphaFoldClinVar (TNNT2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~18.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dilated cardiomyopathy 1DDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011095

Submitter: ClinGen

TNNT2 was originally evaluated for DCM by ClinGen DCM GCEP on August 13, 2020. Evidence of the association of this gene with DCM was re-evaluated on 3/17/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. TNNT2 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2000 (Kamisago et al., 2000, PMID 11106718) Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. At least 10 variants (including missense and nonsense) have been reported in humans with DCM. Of note, the variant p.Lys210del has been reported in multiple unrelated families and been reported in at least one de novo case (Otten et al., 2002, PMID 20978592; Hershberger et al., 2009, PMID 20031601; Morgensen et al., 2004, PMID 15542288). It is considered a recurrent pathogenic variant. In addition, this gene-disease association is supported by animal models, expression studies, and in vitro functional assays. Towsend et al., first showed TNNT2 is expressed in the heart in 1994 (Towsend et al., 1994, PMID 8088824). Animal models include mouse models expressing the variant p.Lys210del which developed DCM and sudden cardiac death (Du et al., 2007, PMID 17556660). Additional evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. TNNT2 has also been curated by the Hypertrophic Cardiomyopathy gene curation expert group for HCM (Definitive, 02/04/2021) and the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (No known disease relationship, 07/16/2019). In summary, TNNT2 is definitively associated with autosomal dominant DCM. 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 Dilated Cardiomyopathy Working Group on August 13, 2020. (SOP Version 7). This written summary was updated on 3/17/2025 and approved by the DCM GCEP on 05/30/2025.

hypertrophic cardiomyopathy 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007267

Submitter: G2P

cardiomyopathy, familial restrictive, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012900

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic cardiomyopathy 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007266

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic cardiomyopathy 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007266

Submitter: Ambry Genetics

dilated cardiomyopathy 1DDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011095

Submitter: Ambry Genetics

cardiomyopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0004994

Submitter: Ambry Genetics

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

familial isolated restrictive cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019150

Submitter: Orphanet

arrhythmogenic right ventricular cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is no evidence that TNNT2 is involved in ARVC. This gene has been investigated for pathogenic variants in two populations of gene-elusive ARVC patients: a study of 84 Chinese gene-elusive ARVC patients and a cohort of 137 North American ARVC patients (29709087). No variants in TNNT2 were reported.

hypertrophic cardiomyopathy 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007266

Submitter: G2P

dilated cardiomyopathy 1DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011095

Submitter: Labcorp Genetics (formerly Invitae)

left ventricular noncompactionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018901

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cardiomyopathy, familial restrictive, 3; Cardiomyopathy, dilated, 1D; Left ventricular noncompaction 6; Cardiomyopathy, familial hypertrophic, 2AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Preventive measures, surveillance (eg, including echocardiography and electrocardiography), and medical management may be helpful to help decrease morbidity

Refs: 7981753; 8205619; 7898523; 9714088; 11106718; 11684629; 15542288; 16651346; 18506004; 18651846; 21483645; 21846512; 22144547; 22292720Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNNT2 variants in ClinVar

31 Conditions Cataloged
Dilated cardiomyopathy 1DTotal: 758
Hypertrophic cardiomyopathy 2Total: 752
Cardiomyopathy, familial restrictive, 3Total: 744
CardiomyopathyTotal: 418
not providedTotal: 306
Cardiovascular phenotypeTotal: 271
not specifiedTotal: 177
TNNT2-related disorderTotal: 77

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001276345.2. 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
3
clinvar
157
clinvar
1
clinvar
 161
missense
13
clinvar
79
clinvar
376
clinvar
10
clinvar
2
clinvar
 480
nonsense
2
clinvar
17
clinvar
 19
start loss
1
clinvar
1
clinvar
 2
frameshift
1
clinvar
1
clinvar
22
clinvar
 24
splice donor/acceptor (+/-2bp)
12
clinvar
28
clinvar
 40
Total14954471673726

Highest pathogenic variant AF is 0.000028748338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001276345.2RefSeqNP_001263274.116MANE Select
ENST00000656932.1EnsemblENSP00000499593.116MANE Select
NM_000364.4RefSeqNP_000355.215Standard
NM_001001430.3RefSeqNP_001001430.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tnnt2aDanio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cardiac muscle contraction - Homo sapiens (human)
  • Dilated cardiomyopathy (DCM) - Homo sapiens (human)
  • Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
  • Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
  • Disopyramide Action Pathway

Biological Process

  • skeletal muscle contraction
  • muscle contraction
  • regulation of heart contraction
  • muscle filament sliding
  • negative regulation of ATPase activity

Molecular Function

  • actin binding
  • calcium ion binding
  • protein binding
  • tropomyosin binding
  • troponin C binding

Cellular Component

  • cytosol
  • troponin complex
  • striated muscle thin filament
  • sarcomere
  • cardiac myofibril

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000509001
Coding exons
15
Length
18755
Individuals with no LoFs
125723
Homozygous LoFs
0
Heterozygous LoFs
25
Defined
125748
p
0.0000994
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.191211640.7380.00001091919
Missense (PolyPhen)4466.3920.66273682
Synonymous0.06175656.60.9900.00000356460
Loss of Function2.92924.60.3650.00000135296

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.000180.00018rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.;
Disease
DISEASE: Cardiomyopathy, familial hypertrophic 2 (CMH2) [MIM:115195]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:10525521, ECO:0000269|PubMed:11034944, ECO:0000269|PubMed:12707239, ECO:0000269|PubMed:12974739, ECO:0000269|PubMed:15563892, ECO:0000269|PubMed:16199542, ECO:0000269|PubMed:21846512, ECO:0000269|PubMed:7898523, ECO:0000269|PubMed:8205619, ECO:0000269|PubMed:8989109, ECO:0000269|PubMed:9060892, ECO:0000269|PubMed:9140840, ECO:0000269|PubMed:9482583, ECO:0000269|Ref.19}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1D (CMD1D) [MIM:601494]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:11106718, ECO:0000269|PubMed:11684629, ECO:0000269|PubMed:15542288, ECO:0000269|PubMed:15769782, ECO:0000269|PubMed:21846512}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial restrictive 3 (RCM3) [MIM:612422]: A heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. {ECO:0000269|PubMed:16651346}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.437

Intolerance Scores

LoFtool
0.0823
RVIS EVS
-0.16
RVIS percentile EVS
41.64

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.859

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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