TNNT1

Chr 19ARAD

troponin T1, slow skeletal type

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

NCBI Gene: 7138 ENSG00000105048 UniProt: P13805 OMIM: 191041

Encodes slow skeletal troponin T, which binds tropomyosin and regulates striated muscle contraction in response to intracellular calcium fluctuations as part of the troponin complex. Mutations cause nemaline myopathy type 5, presenting as severe infantile disease with respiratory insufficiency and death by age 2 years (autosomal recessive) or milder childhood-onset forms (autosomal recessive or dominant inheritance). The pathogenic mechanism involves rod-shaped nemaline inclusions in skeletal muscle fibers leading to progressive muscle weakness.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismAR/ADLOEUF 1.483 OMIM phenotypes

Clinical Summary— TNNT1

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Gene-Disease Validity (ClinGen)

nemaline myopathy 5 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 139 VUS of 442 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TNNT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.99Z-score

OE missense 0.79 (0.69–0.91)

139 obs / 176.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.02 (0.72–1.48)

0≤0.351.4

Missense OE?0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 20 / 19.6Missense obs/exp: 139 / 176.0Syn Z: -0.32

This gene — mechanism propensity

0.79top 25%

GOF

0.5367th %ile

LOF

0.3454th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

442 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic14

VUS139

Likely Benign192

Benign42

Conflicting16

Pathogenic

Likely Pathogenic

139

VUS

192

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	2	9	0	29
Likely Pathogenic	11	2	1	0	14
VUS	2	118	18	1	139
Likely Benign	0	2	133	57	192
Benign	0	1	39	2	42
Conflicting	—				16
Total	31	125	200	60	432

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap TNNT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TNNT1 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — TNNT1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

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

Amyloidosis in Transthyretin (TTR)Amyloidosis, Familial

Comprehensive Program for Hereditary Transthyretin Amyloidosis

RECRUITING

NCT07213297Hospital de Alta Complejidad en RedStarted 2025-11-01

clinical assessments and complementary examinations

Multiple MyelomaAL Amyloidosis

A Phase II Study to Evaluate the Efficacy and Safety of Teclistamab in Combination With Daratumumab (Tec-Dara) in Newly Diagnosed Multiple Myeloma With Concurrent Light Chain Amyloidosis (MM+AL).

RECRUITING

NCT07638683Phase PHASE2Shanghai Zhongshan HospitalStarted 2026-05-22

Teclistamab

Systemic AmyloidosisATTR AmyloidosisAL Amyloidosis

Hungarian National Systemic Amyloidosis Registry

RECRUITING

NCT07689331Semmelweis UniversityStarted 2026-03-08

TNNT1-associated MyopathyInfantile-onset Nemaline Rod MyopathyMyopathies, Nemaline

WiTNNess - TNNT1 Myopathy Natural History Study

RECRUITING

NCT06374719Clinic for Special ChildrenStarted 2018-09-23

IUGRFetal Growth RetardationIntrauterine Growth Restriction