TNNT1

Chr 19ARAD

troponin T1, slow skeletal type

Also known as: ANM, NEM5, STNT, TNT, TNTS

NCBI Gene: 7138ENSG00000105048UniProt: P13805

This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Nemaline myopathy 5A, autosomal recessive, severe infantileMIM #605355
AR
Nemaline myopathy 5B, autosomal recessive, childhood-onsetMIM #620386
AR
Nemaline myopathy 5C, autosomal dominantMIM #620389
AD
461
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— TNNT1
🧬
Gene-Disease Validity (ClinGen)
nemaline myopathy 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 150 VUS of 461 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.48LOEUF
pLI 0.000
Z-score -0.08
OE 1.02 (0.72–1.48)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.99Z-score
OE missense 0.79 (0.69–0.91)
139 obs / 176.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.02 (0.72–1.48)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.69–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 20 / 19.6Missense obs/exp: 139 / 176.0Syn Z: -0.32

ClinVar Variant Classifications

461 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic16
VUS150
Likely Benign192
Benign42
Conflicting16
45
Pathogenic
16
Likely Pathogenic
150
VUS
192
Likely Benign
42
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
2
33
0
45
Likely Pathogenic
9
2
5
0
16
VUS
2
118
29
1
150
Likely Benign
0
2
133
57
192
Benign
0
1
39
2
42
Conflicting
—16
Total2112523960461

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

View in ClinVar →

Protein Context — Lollipop Plot

TNNT1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Nemaline myopathy 5A, autosomal recessive, severe infantile

MIM #605355

Molecular basis of disorder known

Autosomal recessive

Nemaline myopathy 5B, autosomal recessive, childhood-onset

MIM #620386

Molecular basis of disorder known

Autosomal recessive

Nemaline myopathy 5C, autosomal dominant

MIM #620389

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TNNT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Epigenetic regulation of TNNT1 in gastrointestinal cancers prognostic implications and clinical significance.
Xie J et al.·Clin Epigenetics
2025
Congenital myopathies: pathophysiological mechanisms and promising therapies.
Zhang H et al.·J Transl Med
2024Review
[Congenital myopathies].
Cabello A et al.·Rev Neurol
2003Review
Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.
Laitila J et al.·J Physiol
2025
A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy.
Ogasawara M et al.·Neuromuscul Disord
2021Review
TNNT1 accelerates migration, invasion and EMT progression in lung cancer cells.
Ge X et al.·Thorac Cancer
2024
High extracellular matrix stiffness upregulates TNNT1 to awaken dormant tumor cells in liver metastatic niches of gastric cancer.
Ji L et al.·Cell Oncol (Dordr)
2025
TNNT1 nemaline myopathy: natural history and therapeutic frontier.
Fox MD et al.·Hum Mol Genet
2018Natural history
Tropomyosins in skeletal muscle diseases.
Kee AJ et al.·Adv Exp Med Biol
2008Review
Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.
Pellerin D et al.·Ann Neurol
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Chronic Heart FailureAging

Comparing the Effects of Combining Cognitive and Physical Exercise Training on Cognition, and Cerebral Blood Flow Regulation in Men and Women With Chronic Heart Failure

RECRUITING
NCT04970888Phase NAMontreal Heart InstituteStarted 2021-09-01
Cognitive trainingExercise trainingUsual care
TNNT1-associated MyopathyInfantile-onset Nemaline Rod MyopathyMyopathies, Nemaline

WiTNNess - TNNT1 Myopathy Natural History Study

RECRUITING
NCT06374719Clinic for Special ChildrenStarted 2018-09-23
Hereditary Amyloidosis, Transthyretin-Related

Phenotypic Manifestations of Hereditary ATTR Amyloidosis

ENROLLING BY INVITATION
NCT07124377Hospital 9 de Julio de Las BreñasStarted 2024-09-01
A complete physical examination of all body systems, including height and body weightNeurological examination includes motor strength testing; sensory testing with pinprick, light touch, temperature, and proprioception; deep tendon reflexes; and gait assessment.Electrocardiogram (12-lead ECG)
Heart FailureDilated Cardiomyopathy

Myocardial Telomere Recapping Study for Dilated Cardiomyopathy

ACTIVE NOT RECRUITING
NCT05837143Phase EARLY_PHASE1Shanghai East HospitalStarted 2023-03-30
JV001
Giant Cell ArteritisPolymyalgia Rheumatica

Assessing Biomarker in Giant Cell Arteritis and Polymyalgia Rheumatic

RECRUITING
NCT06460142University of BonnStarted 2023-09-01
Aortic/ cardiac magnetic resonance imagingVascular ultrasoundTransorbital Ultrasound
Silent Myocardial IschemiaAcute Myocardial Infarction

Silent Myocardial Ischemia in Patients Undergoing Non-oncological Abdominal Surgeries

RECRUITING
NCT06536686University Medical Centre LjubljanaStarted 2024-07-01
Silent myocardial ischemia, STEMI
Muscular DystrophyDuchenne Muscular DystrophyBecker Muscular Dystrophy

Follow-up Study on Female Carriers With DMD Gene Variants

ENROLLING BY INVITATION
NCT05715957Rigshospitalet, DenmarkStarted 2023-05-18
No intervention
IUGRFetal Growth RetardationIntrauterine Growth Restriction

Cardiac Displacement From Third Trimester to Early Childhood

ACTIVE NOT RECRUITING
NCT02583763University Hospital, LinkoepingStarted 2013-01
EchocardiographyBlood sample
Heart FailureAmyloid CardiomyopathyATTR Amyloidosis Wild Type

EOSS-ATTR Study (eHealth Based Operative Support System in ATTR-CM)

NOT YET RECRUITING
NCT06499064Phase NAHospital Universitari de BellvitgeStarted 2024-12-01
mHealth
ResilienceCognitive Function and Well-BeingMuscle Function, Handgrip Strength Test

Aging Resilience Through Microbiota Optimization and Regulation

ACTIVE NOT RECRUITING
NCT06649981Phase PHASE1Gonzalo Jorquera, PhDStarted 2025-01-10
FMT capsulePlacebo Capsule(s)
Transthyretin AmyloidosisATTR-CMATTRv-PN

Non-interventional Study of Patients With Transthyretin (ATTR) Amyloidosis

RECRUITING
NCT06465810AstraZenecaStarted 2024-06-25
Treatment of transthyretin (ATTR) amyloidosis in observational study setting
Cardiomyopathy, DilatedBcl-2 Anathogene-3 (BAG3) Dilated Cardiomyopathy (DCM)

A Study About the Natural History in Adults With BAG3 Dilated Cardiomyopathy (a Type of Heart Disease) (BAG3 DCM)

ACTIVE NOT RECRUITING
NCT05981092Alexion Pharmaceuticals, Inc.Started 2022-10-14

External Resources

Links to major genomics databases and tools