GeneBe

TNNT3

protein-coding

troponin T3, fast skeletal type, the group of Troponin complex subunits

Gene summary

The binding of Ca(2+) to the trimeric troponin complex initiates the process of muscle contraction. Increased Ca(2+) concentrations produce a conformational change in the troponin complex that is transmitted to tropomyosin dimers situated along actin filaments. The altered conformation permits increased interaction between a myosin head and an actin filament which, ultimately, produces a muscle contraction. The troponin complex has protein subunits C, I, and T. Subunit C binds Ca(2+) and subunit I binds to actin and inhibits actin-myosin interaction. Subunit T binds the troponin complex to the tropomyosin complex and is also required for Ca(2+)-mediated activation of actomyosin ATPase activity. There are 3 different troponin T genes that encode tissue-specific isoforms of subunit T for fast skeletal-, slow skeletal-, and cardiac-muscle. This gene encodes fast skeletal troponin T protein; also known as troponin T type 3. Alternative splicing results in multiple transcript variants encoding additional distinct troponin T type 3 isoforms. A developmentally regulated switch between fetal/neonatal and adult troponin T type 3 isoforms occurs. Additional splice variants have been described but their biological validity has not been established. Mutations in this gene may cause distal arthrogryposis multiplex congenita type 2B (DA2B). [provided by RefSeq, Oct 2009]

MANE transcript

NM_006757.4

Inheritance

AR, AD

ClinVar variants

P:8U:114B:46

Top phenotype

Arthyrgryposis, distal, type 2B2

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr11:1,919,703-1,938,706

External References & Databases

Ensembl (ENSG00000130595)NCBI Gene (7140)OMIM (600692)HGNC:11950GenCCUniProt (P45378)AlphaFoldClinVar (TNNT3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~19.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: G2P

Sheldon-hall syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011128

Submitter: Orphanet

nemaline myopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018958

Submitter: ClinGen

*TNNT3* was first reported in relation to autosomal recessive nemaline myopathy in 2018 (Sandaradura SA, et al., 2018, PMID: 29266598). Evidence supporting this gene-disease relationship includes case-level data and segregation data. Two splice variant has been reported in two patients in two publicatsions (PMIDs: 29266598, 33977145). This gene-disease association is supported by its biochemical function in muscle contraction (PMID: 7721095), its interaction with *TNNT1* (PMID: 6447509), its expression in skeletal muscle (PMID: 23775847), and a neonatal lethal mouse model (PMID: 23775847). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Of note, this gene has also been implicated in autosomal dominant distal arthrogryposis which will be assessed separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism (loss of function for nemaline myopathy versus a functional alteration due to missense variation at Arg63 for autosomal dominant distal arthrogryposis), inheritance pattern (dominant versus recessive), phenotypic variability (presence of nemaline myopathy and absence of facial features associated with autosomal dominant distal arthrogryposis). Therefore, we have split curations for the disease entities of autosomal recessive nemaline myopathy and autosomal dominant distal arthrogryposis. This gene-disease pair was originally evaluated by the CM GCEP on 02/24/2020. It was reevaluated on 02/21/2025. As a result of this reevaluation new genetic evidence (PMID: 33977145) was identified however the classification remained at Limited. This second case provided additional evidnece for a gene-diseae relationship with a congenital myopathy though the patient did not have nemaline rods.

distal arthrogryposis type 2B1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020820

Submitter: Labcorp Genetics (formerly Invitae)

digitotalar dysmorphismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015240

Submitter: Orphanet

arthrogryposis, distal, type 2B2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032750

Submitter: PanelApp Australia

arthrogryposis, distal, type 2B2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032750

Submitter: Ambry Genetics

nemaline myopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018958

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Arthyrgryposis, distal, type 2B2AD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12865991Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNNT3 variants in ClinVar

9 Conditions Cataloged
not providedTotal: 243
Inborn genetic diseasesTotal: 35
not specifiedTotal: 30
TNNT3-related disorderTotal: 19
Arthrogryposis, distal, type 2B2Total: 12
Distal arthrogryposis type 2B1Total: 11
Congenital myopathyTotal: 2
Sheldon-Hall syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006757.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
30
clinvar
5
clinvar
 38
missense
4
clinvar
99
clinvar
8
clinvar
2
clinvar
 113
nonsense
1
clinvar
3
clinvar
 4
start loss
0
frameshift
2
clinvar
 2
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
7
clinvar
1
clinvar
 11
Total26114388168

Highest pathogenic variant AF is 0.00004215355

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 211 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006757.4RefSeqNP_006748.115MANE Select
ENST00000278317.11EnsemblENSP00000278317.615MANE Select
NM_001042780.3RefSeqNP_001036245.114Standard
NM_001042781.3RefSeqNP_001036246.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tnnt3bDanio rerio

Structure: fast muscle cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Disopyramide Action Pathway
  • Procainamide (Antiarrhythmic) Action Pathway
  • Phenytoin (Antiarrhythmic) Action Pathway
  • Fosphenytoin (Antiarrhythmic) Action Pathway
  • Bopindolol Action Pathway

Biological Process

  • skeletal muscle contraction
  • muscle contraction
  • regulation of striated muscle contraction
  • muscle filament sliding
  • regulation of ATPase activity

Molecular Function

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

Cellular Component

  • cytosol
  • troponin complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000278317
Coding exons
15
Length
19145
Individuals with no LoFs
125724
Homozygous LoFs
0
Heterozygous LoFs
24
Defined
125748
p
0.0000954
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.4631301460.8920.000009991723
Missense (PolyPhen)4754.6780.85958658
Synonymous-0.6445751.11.110.00000356412
Loss of Function1.651422.40.6240.00000121279

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.0000890.000087rare
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000710.000070rare
South Asian0.000200.00020rare
Other0.000170.00016rare

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.;

Recessive Scores

pRec
0.157

Intolerance Scores

LoFtool
0.214
RVIS EVS
-0.41
RVIS percentile EVS
26.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.660

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.