TNNT1

Summary

TNNT1 (troponin T1, slow skeletal type, HGNC:11948) is a protein-coding gene on chromosome 19q13.42, encoding Troponin T, slow skeletal muscle (P13805). Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

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.

Source: NCBI Gene 7138 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nemaline myopathy 5 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 419 total — 23 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 69
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11948
Approved symbol	TNNT1
Name	troponin T1, slow skeletal type
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	ANM, STNT, TNT, TNTS, FLJ98147, MGC104241, NEM5
Ensembl gene	ENSG00000105048
Ensembl biotype	protein_coding
OMIM	191041
Entrez	7138

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 24 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000291901, ENST00000356783, ENST00000585321, ENST00000586282, ENST00000586649, ENST00000587089, ENST00000587465, ENST00000587758, ENST00000588147, ENST00000588426, ENST00000588981, ENST00000589226, ENST00000589745, ENST00000592920, ENST00000593046, ENST00000593194, ENST00000964355, ENST00000964356, ENST00000964357, ENST00000964358, ENST00000964359, ENST00000964360, ENST00000964361, ENST00000964362, ENST00000964363, ENST00000964364, ENST00000964365

RefSeq mRNA: 4 — MANE Select: NM_003283 NM_001126132, NM_001126133, NM_001291774, NM_003283

CCDS: CCDS12917, CCDS46185, CCDS59421

Canonical transcript exons

ENST00000588981 — 14 exons

Exon	Start	End
ENSE00001052423	55134066	55134204
ENSE00002834608	55149161	55149206
ENSE00003492176	55133887	55133927
ENSE00003493043	55141857	55141920
ENSE00003510618	55145544	55145565
ENSE00003525631	55146434	55146466
ENSE00003552244	55140883	55140960
ENSE00003574697	55141186	55141302
ENSE00003633133	55146681	55146707
ENSE00003661403	55147126	55147168
ENSE00003678675	55147008	55147021
ENSE00003681555	55137961	55138074
ENSE00003789397	55137103	55137212
ENSE00003851054	55132698	55132960

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.8815 / max 28202.4481, expressed in 1019 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182711	53.3660	336
182700	5.1011	771
182696	1.0066	377
182698	0.9571	353
182693	0.8389	144
182702	0.4551	191
182695	0.4340	78
182699	0.4306	229
182691	0.3884	45
182701	0.3524	130

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	99.99	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.97	gold quality
diaphragm	UBERON:0001103	99.96	gold quality
triceps brachii	UBERON:0001509	99.96	gold quality
gastrocnemius	UBERON:0001388	99.93	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.92	gold quality
skeletal muscle tissue	UBERON:0001134	99.89	gold quality
biceps brachii	UBERON:0001507	99.89	gold quality
vastus lateralis	UBERON:0001379	99.88	gold quality
quadriceps femoris	UBERON:0001377	99.87	gold quality
tibialis anterior	UBERON:0001385	99.84	gold quality
deltoid	UBERON:0001476	99.84	gold quality
body of tongue	UBERON:0011876	99.54	gold quality
apex of heart	UBERON:0002098	99.43	gold quality
muscle organ	UBERON:0001630	98.58	gold quality
muscle of leg	UBERON:0001383	98.07	gold quality
heart left ventricle	UBERON:0002084	96.70	gold quality
cardiac ventricle	UBERON:0002082	96.35	gold quality
right atrium auricular region	UBERON:0006631	94.21	gold quality
muscle tissue	UBERON:0002385	93.66	gold quality
tongue	UBERON:0001723	93.27	gold quality
cardiac atrium	UBERON:0002081	93.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.88	gold quality
heart	UBERON:0000948	91.04	gold quality
skin of abdomen	UBERON:0001416	91.01	gold quality
skin of leg	UBERON:0001511	90.72	gold quality
right frontal lobe	UBERON:0002810	90.30	gold quality
cingulate cortex	UBERON:0003027	90.01	gold quality
anterior cingulate cortex	UBERON:0009835	89.93	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1256.42
E-CURD-98	yes	1073.61
E-HCAD-13	yes	1020.47
E-MTAB-10485	yes	561.60
E-MTAB-8221	yes	242.27
E-MTAB-8271	yes	181.52
E-MTAB-8205	yes	117.23
E-MTAB-11121	yes	70.41
E-MTAB-8410	yes	22.09
E-MTAB-11268	no	1019.08
E-MTAB-6524	no	313.23
E-GEOD-36552	no	115.87
E-GEOD-124858	no	16.00
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA4, MEF2A, SP1

miRNA regulators (miRDB)

7 targeting TNNT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-580-5P	99.28	70.94	1776

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that inefficient incorporation into myofilament is responsible for the instability of mutant slow troponin T in Amish nemaline myopathy. (PMID:15665378)
• Report adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease. (PMID:18579801)
• slow TnT was encoded by two different transcripts in significantly different ratios in myotonic dystrophy type 1 and myotonic dystrophy type 2 muscles. (PMID:19326042)
• Troponin T may have a role in pulmonary embolism progeresion to death (PMID:19541721)
• TNT is a biochemical marker of susceptibility to hypoxia in infants of type 1 diabetic mothers. (PMID:19690080)
• The occurrence of myocardial infarction is associated with elevated troponin T levels. (PMID:19916752)
• troponin-T mutations were responsible for 3% of the hypertrophic cardiomyopathy cases in our study population (PMID:20038417)
• Among athletees, faster runners demonstrate significantly stronger cardoac TnT releases and inflammation signs. (PMID:20380359)
• analysis of order and disorder in troponin C, T and I (PMID:20889975)
• Elevated serum troponin T levels are associated with different conditions related to the severity of hypertrophic cardiomyopathy. (PMID:21111984)
• Cardiac troponin T and creatine kinase have roles in infarct size and left ventricular function after acute myocardial infarction (PMID:21448949)
• the hypertrophic phenotype associated with the TnT mutations can be characterized by a significant increase in disorder of rigor cross-bridges. (PMID:21683708)
• In heart failure patients with normal ejection fraction, highly sensitive troponin T and heart fatty acid binding protein are elevated independent of coronary artery disease. (PMID:21729325)
• carotid-femoral pulse wave and office pulse pressure are associated with minimally elevated hsTnT levels in the elderly (PMID:21784424)
• baseline cTnT levels are higher in patients with MPI evidence of reversible myocardial ischaemia than those without reversible ischaemia (PMID:22239123)
• analysis of parameters of oxygen-dependent metabolism of neutrophils by NBT test and levels of vWF antigen in the serum can be used for predicting the risk of unfavorable outcome in patients with ACS and normal troponin T (PMID:22448368)
• Human slow skeletal troponin T (HSSTnT) isoforms, despite being homologues of cardiac TnT may display distinct functional properties in muscle regulation. (PMID:22977240)
• TNNT1 DNA methylation levels were positively correlated with mean HDL particle size, HDL-phospholipid, HDL-apolipoprotein AI, HDL-C and TNNT1 expression levels. (PMID:23244308)
• Troponin T1 blood levels had a positive association with increased risk for hypertrophic cardiomyopathy. (PMID:24020864)
• troponin T and creatinine kinase isoenzyme (CK-MB) have roles in combined renal and myocardial injuries in asphyxiated infants (PMID:24625749)
• Biopsy-proven acute and viral myocarditis is associated with elevated concentrations of hs-TnT. (PMID:24781421)
• Nemaline body myopathy Palestinian patients were found to have a novel mutation in troponin T1. (PMID:26296490)
• Three homologous genes have evolved in vertebrates to encode three muscle type-specific TnT isoforms: TNNT1 for slow skeletal muscle TnT, TNNT2 for cardiac muscle TnT, and TNNT3 for fast skeletal muscle TnT. (PMID:26774798)
• TNNT1 genetic and epigenetic variations are associated with HDL-C levels and coronary artery disease. (PMID:26950807)
• pathogenesis of TNNT1 myopathies (PMID:27429059)
• Copeptin and troponin T measurement could potentially improve the prehospital diagnostic and prognostic classification of patients with a suspected AMI. (PMID:27903076)
• Data suggest that mutations in troponin C (TnC, A8V) and troponin T (TnT, delta14-TnT) found in patients with hypertrophic cardiomyopathy together fully stabilize the active M state of regulated actin (the actin-tropomyosin-troponin complex). (PMID:28530094)
• investigated the effects of one of these mutations, K247R of TnT, on the picosecond dynamics of the Tn core domain (Tn-CD), consisting of TnC, TnI and TnT2 (183-288 residues of TnT), by carrying out the quasielastic neutron scattering measurements on the reconstituted Tn-CD containing either the wild-type TnT2 (wtTn-CD) or the mutant TnT2 (K247R-Tn-CD) in the absence and presence of Ca(2+) (PMID:28923663)
• This study describes the first TNNT1 mutation that transmits in an autosomal dominant fashion to cause nemaline myopathy. (PMID:29178646)
• In a nationwide cohort in Sweden, patients with a first myocardial infarction had increased levels of Troponin T. (PMID:29880121)
• Similar functional and histological phenotypes were observed in other human cohorts and two transgenic murine models (Tnnt1-/- and Tnnt1 c.505G>T). These findings have implications for emerging molecular therapies, including the suitably of TNNT1 gene replacement for newborns with ‘Amish’ nemaline myopathy or other TNNT1-associated myopathies. (PMID:29931346)
• High TNNT1 expression is associated with breast cancer. (PMID:30031058)
• These findings indicated that TNNT1 may promote the progression of colon adenocarcinoma, mediating epithelial-mesenchymal transition process, and thus shed a novel light on colon adenocarcinoma therapeutic treatments. (PMID:31512553)
• TNNT1, negatively regulated by miR-873, promotes the progression of colorectal cancer. (PMID:31830337)
• Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). This study expands the phenotypic spectrum of TNNT1 myopathy. (PMID:31970803)
• Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy. (PMID:32994279)
• Troponin T but not C reactive protein is associated with future surgery for aortic stenosis: a population-based nested case-referent study. (PMID:33051334)
• Biomarkers-in-Cardiology 8 RE-VISITED-Consistent Safety of Early Discharge with a Dual Marker Strategy Combining a Normal hs-cTnT with a Normal Copeptin in Low-to-Intermediate Risk Patients with Suspected Acute Coronary Syndrome-A Secondary Analysis of the Randomized Biomarkers-in-Cardiology 8 Trial. (PMID:35053326)
• TNNT1 myopathy with novel compound heterozygous mutations. (PMID:35165004)
• Slow skeletal muscle troponin T acts as a potential prognostic biomarker and therapeutic target for hepatocellular carcinoma. (PMID:36871674)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnnt1	ENSDARG00000037954
mus_musculus	Tnnt1	ENSMUSG00000064179
rattus_norvegicus	Tnnt1	ENSRNOG00000028041
drosophila_melanogaster	up	FBGN0004169
caenorhabditis_elegans		WBGENE00006588

Paralogs (2): TNNT2 (ENSG00000118194), TNNT3 (ENSG00000130595)

Protein

Protein identifiers

Troponin T, slow skeletal muscle — P13805 (reviewed: P13805)

Alternative names: Slow skeletal muscle troponin T

All UniProt accessions (10): P13805, K7EKB5, K7EKM3, K7ELB0, K7EQL4, M0QX01, M0QY38, M0QZU8, M0QZY5, Q3B759

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with TPM3.

Disease relevance. Nemaline myopathy 5A, autosomal recessive, severe infantile (NEM5A) [MIM:605355] A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM5A is a severe and progressive form characterized by symptom onset soon after birth or in early infancy. Affected infants display tremors with hypotonia and mild contractures of the shoulders and hips. Proximal contractures progressively weaken and a pectus carinatum deformity develops before children die of respiratory insufficiency, usually in the second year. The disease is caused by variants affecting the gene represented in this entry. Nemaline myopathy 5B, autosomal recessive, childhood-onset (NEM5B) [MIM:620386] A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM5B is characterized by proximal muscle weakness of the lower and upper limbs, gait abnormalities, and delayed motor development in some affected individuals. Most patients remain ambulatory even into late adulthood and develop restrictive respiratory insufficiency with decreased forced vital capacity. The disease is caused by variants affecting the gene represented in this entry. Nemaline myopathy 5C, autosomal dominant (NEM5C) [MIM:620389] A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM5C is a relatively mild skeletal muscle disorder appearing in the first or second decades. Main clinical features include difficulty walking on the heels, waddling gait, proximal muscle weakness affecting the upper and lower limbs, and Gowers sign. Patients remain ambulatory into late adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the troponin T family.

Isoforms (3)

UniProt ID	Names	Canonical?
P13805-1	1	yes
P13805-2	2
P13805-3	3

RefSeq proteins (4): NP_001119604, NP_001119605, NP_001278703, NP_003274* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001978	Troponin	Family
IPR027707	TNNT	Family
IPR038077	Troponin_sf	Homologous_superfamily

Pfam: PF00992

UniProt features (17 total): sequence variant 7, compositionally biased region 3, region of interest 2, splice variant 2, chain 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13805-F1	74.89	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction

MSigDB gene sets: 321 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_SKELETAL_MUSCLE_ADAPTATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, GOBP_SARCOMERE_ORGANIZATION, GOBP_SKELETAL_MUSCLE_CONTRACTION, CAGCTG_AP4_Q5, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_MUSCLE_CONTRACTION

GO Biological Process (7): skeletal muscle contraction (GO:0003009), transition between fast and slow fiber (GO:0014883), slow-twitch skeletal muscle fiber contraction (GO:0031444), sarcomere organization (GO:0045214), negative regulation of muscle contraction (GO:0045932), regulation of muscle contraction (GO:0006937), striated muscle contraction (GO:0006941)

GO Molecular Function (5): tropomyosin binding (GO:0005523), troponin T binding (GO:0031014), protein binding (GO:0005515), troponin C binding (GO:0030172), troponin I binding (GO:0031013)

GO Cellular Component (2): cytosol (GO:0005829), troponin complex (GO:0005861)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeletal protein binding	4
muscle contraction	3
striated muscle contraction	1
musculoskeletal movement	1
regulation of skeletal muscle adaptation	1
twitch skeletal muscle contraction	1
myofibril assembly	1
actomyosin structure organization	1
regulation of muscle contraction	1
negative regulation of multicellular organismal process	1
regulation of muscle system process	1
binding	1
cytoplasm	1
cellular anatomical structure	1
striated muscle thin filament	1
protein-containing complex	1

Protein interactions and networks

STRING

1242 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNNT1	TNNI1	P19237	967
TNNT1	TNNI2	P48788	949
TNNT1	TNNI3	P19429	934
TNNT1	KBTBD13	C9JR72	932
TNNT1	TPM2	P06468	915
TNNT1	TPM1	P09493	860
TNNT1	TNNC1	P02590	833
TNNT1	MYH7	P12883	832
TNNT1	TPM3	P06753	824
TNNT1	ACTA1	P02568	800
TNNT1	NEB	P20929	772
TNNT1	CDON	Q4KMG0	769
TNNT1	KLHL40	Q2TBA0	726
TNNT1	MYL2	P10916	696
TNNT1	CFL2	Q9Y281	685

IntAct

90 interactions, top by confidence:

A	B	Type	Score
TNNT1	LDOC1	psi-mi:“MI:0915”(physical association)	0.670
TNNT1	TPM1	psi-mi:“MI:0915”(physical association)	0.670
TNNT1	NFE2L2	psi-mi:“MI:0915”(physical association)	0.670
TFIP11	TNNT1	psi-mi:“MI:0915”(physical association)	0.670
TPM1	TNNT1	psi-mi:“MI:0915”(physical association)	0.670
NFE2L2	TNNT1	psi-mi:“MI:0915”(physical association)	0.670
TNNT1	TFIP11	psi-mi:“MI:0915”(physical association)	0.670
TNNT1	KRT40	psi-mi:“MI:0915”(physical association)	0.560
CCDC136	TNNT1	psi-mi:“MI:0915”(physical association)	0.560
TNNT1	TBPL1	psi-mi:“MI:0915”(physical association)	0.560
TNNT1	TPM3	psi-mi:“MI:0915”(physical association)	0.560
MORF4L1	TNNT1	psi-mi:“MI:0915”(physical association)	0.560
TBPL1	TNNT1	psi-mi:“MI:0915”(physical association)	0.560
TPM3	TNNT1	psi-mi:“MI:0915”(physical association)	0.560
TNNT1	MORF4L1	psi-mi:“MI:0915”(physical association)	0.560
KRT40	TNNT1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (94): TNNT1 (Two-hybrid), TNNT1 (Two-hybrid), TPM1 (Two-hybrid), TPM3 (Two-hybrid), TBPL1 (Two-hybrid), MORF4L1 (Two-hybrid), LDOC1 (Two-hybrid), TFIP11 (Two-hybrid), CCDC136 (Two-hybrid), KRT40 (Two-hybrid), CCDC85B (Two-hybrid), PLEKHF1 (Two-hybrid), PPFIA1 (Two-hybrid), TNNT1 (Two-hybrid), ZMYND19 (Two-hybrid)

ESM2 similar proteins: A0A096LP55, A0A1D8PJT8, A1L243, A1L3N6, A6H767, A9ULB4, P00126, P00429, P05067, P07919, P08592, P12023, P13805, P14854, P23025, P27088, P28656, P36233, P36378, P48504, P55209, P56277, P79307, P99028, Q0P451, Q0VBY0, Q15545, Q28CA1, Q28EB4, Q2HJG8, Q4R374, Q4R5A5, Q4U0Y4, Q53CG4, Q5IS80, Q5M9I5, Q5R4D4, Q5R7L9, Q5RCT0, Q64267

Diamond homologs: O88346, P02641, P02642, P06398, P09739, P09741, P12620, P13789, P13805, P19351, P45378, P45379, P50751, P50752, P50753, Q75NG9, Q75ZZ6, Q7TNB2, Q8MKH6, Q8MKI3, Q9QZ47, Q9XZ71

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	8	7.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

419 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	10
Uncertain significance	129
Likely benign	179
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
12440	NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter)	Pathogenic
1285366	NM_003283.6(TNNT1):c.607_610delinsTAGTGCTGT (p.Leu203_Arg204delinsTer)	Pathogenic
1325207	NM_003283.6(TNNT1):c.611+1dup	Pathogenic
1413567	NC_000019.9:g.(?55652544)(55656943_?)del	Pathogenic
1452357	NM_003283.6(TNNT1):c.78del (p.Glu27fs)	Pathogenic
1456474	NM_003283.6(TNNT1):c.415G>T (p.Glu139Ter)	Pathogenic
167737	NM_003283.6(TNNT1):c.323C>G (p.Ser108Ter)	Pathogenic
2004473	NM_003283.6(TNNT1):c.626G>A (p.Trp209Ter)	Pathogenic
2104989	NM_003283.6(TNNT1):c.61dup (p.Glu21fs)	Pathogenic
2503493	NC_000019.10:g.(?55132793)(55132961_55133886)del	Pathogenic
2503494	NM_003283.6(TNNT1):c.334G>T (p.Glu112Ter)	Pathogenic
2503496	NM_003283.6(TNNT1):c.16G>T (p.Glu6Ter)	Pathogenic
2503497	NM_003283.6(TNNT1):c.611+1G>A	Pathogenic
2503499	NM_003283.6(TNNT1):c.724G>C (p.Ala242Pro)	Pathogenic
3248446	NC_000019.9:g.(?55652231)(55658525_?)del	Pathogenic
3248447	NC_000019.9:g.(?55644283)(55653308_?)del	Pathogenic
3620500	NM_003283.6(TNNT1):c.431del (p.Ala144fs)	Pathogenic
3679087	NM_003283.6(TNNT1):c.7_13dup (p.Glu5fs)	Pathogenic
3775958	NM_003283.6(TNNT1):c.502_505del	Pathogenic
534399	NM_003283.6(TNNT1):c.120dup (p.Lys41fs)	Pathogenic
870626	NM_003283.6(TNNT1):c.353del (p.Thr118fs)	Pathogenic
872190	NM_003283.6(TNNT1):c.739C>T (p.Gln247Ter)	Pathogenic
949099	NM_003283.6(TNNT1):c.695dup (p.Leu233fs)	Pathogenic
1066598	NM_003283.6(TNNT1):c.501+1G>A	Likely pathogenic
1481323	NM_003283.6(TNNT1):c.387+1G>A	Likely pathogenic
1878625	NM_003283.6(TNNT1):c.742A>T (p.Lys248Ter)	Likely pathogenic
2010722	NM_003283.6(TNNT1):c.310-2A>T	Likely pathogenic
2500959	NM_003283.6(TNNT1):c.74-67C>A	Likely pathogenic
2664155	NM_003283.6(TNNT1):c.272_281del (p.Lys91fs)	Likely pathogenic
2858894	NM_003283.6(TNNT1):c.33-1G>A	Likely pathogenic

SpliceAI

2074 predictions. Top by Δscore:

Variant	Effect	Δscore
19:55133886:CAA:C	donor_gain	1.0000
19:55134060:TCTCA:T	donor_loss	1.0000
19:55134061:CTCAC:C	donor_loss	1.0000
19:55134062:TCA:T	donor_loss	1.0000
19:55134063:CA:C	donor_loss	1.0000
19:55134064:A:AC	donor_gain	1.0000
19:55134065:C:CC	donor_gain	1.0000
19:55134065:CCT:C	donor_gain	1.0000
19:55137209:CTGC:C	acceptor_gain	1.0000
19:55137210:TGC:T	acceptor_gain	1.0000
19:55137213:C:CC	acceptor_gain	1.0000
19:55137213:CTGAG:C	acceptor_loss	1.0000
19:55137219:G:C	acceptor_gain	1.0000
19:55137956:CTCA:C	donor_loss	1.0000
19:55137959:A:AC	donor_gain	1.0000
19:55137959:AC:A	donor_gain	1.0000
19:55137959:ACCTT:A	donor_loss	1.0000
19:55137960:C:CC	donor_gain	1.0000
19:55137960:CC:C	donor_gain	1.0000
19:55138070:TCCTC:T	acceptor_gain	1.0000
19:55138071:CCTCC:C	acceptor_gain	1.0000
19:55138072:CTC:C	acceptor_gain	1.0000
19:55138073:TC:T	acceptor_gain	1.0000
19:55138074:CC:C	acceptor_gain	1.0000
19:55138074:CCTG:C	acceptor_loss	1.0000
19:55138075:C:CC	acceptor_gain	1.0000
19:55140892:AG:A	donor_gain	1.0000
19:55140893:G:C	donor_gain	1.0000
19:55141113:T:C	donor_gain	1.0000
19:55141177:T:A	donor_gain	1.0000

AlphaMissense

1824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:55141237:G:C	F86L	1.000
19:55141237:G:T	F86L	1.000
19:55141239:A:G	F86L	1.000
19:55141242:G:C	H85D	1.000
19:55141253:A:G	L81P	1.000
19:55141262:A:G	L78P	1.000
19:55141287:G:T	R70S	1.000
19:55133908:C:G	R257P	0.999
19:55134102:G:C	F238L	0.999
19:55134102:G:T	F238L	0.999
19:55134104:A:G	F238L	0.999
19:55138012:T:A	K150N	0.999
19:55138012:T:G	K150N	0.999
19:55140953:C:G	R106P	0.999
19:55141190:C:G	R102P	0.999
19:55141229:C:G	R89P	0.999
19:55141238:A:C	F86C	0.999
19:55141238:A:G	F86S	0.999
19:55141240:A:C	H85Q	0.999
19:55141240:A:T	H85Q	0.999
19:55141242:G:T	H85N	0.999
19:55141250:A:T	I82N	0.999
19:55141262:A:T	L78Q	0.999
19:55141271:A:G	L75P	0.999
19:55141273:G:C	D74E	0.999
19:55141273:G:T	D74E	0.999
19:55141274:T:A	D74V	0.999
19:55141274:T:C	D74G	0.999
19:55141274:T:G	D74A	0.999
19:55141275:C:G	D74H	0.999

dbSNP variants (sampled 300 via entrez): RS1000052845 (19:55142416 C>A,T), RS1000235168 (19:55149214 C>T), RS1000395661 (19:55148381 A>G), RS1000447143 (19:55132232 G>A), RS1000916735 (19:55132457 G>A,C), RS1001002451 (19:55146752 G>A,C), RS1001222019 (19:55149853 C>G), RS1001293367 (19:55144231 C>A), RS1001315433 (19:55138404 A>G,T), RS1001363245 (19:55135921 C>T), RS1001459843 (19:55146513 G>A,C,T), RS1001616194 (19:55138867 G>A), RS1001673528 (19:55149277 G>C), RS1001785913 (19:55149633 G>A), RS1002119422 (19:55148692 A>C)

Disease associations

OMIM: gene MIM:191041 | disease phenotypes: MIM:605355, MIM:620389, MIM:620386

GenCC curated gene-disease

Disease	Classification	Inheritance
nemaline myopathy 5	Strong	Autosomal recessive
nemaline myopathy 5B, autosomal recessive, childhood-onset	Strong	Autosomal recessive
nemaline myopathy 5C, autosomal dominant	Limited	Autosomal dominant
nemaline myopathy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nemaline myopathy 5	Definitive	AR
nemaline myopathy	Limited	AD

Mondo (5): nemaline myopathy 5 (MONDO:0011539), myopathy (MONDO:0005336), nemaline myopathy 5C, autosomal dominant (MONDO:0957284), nemaline myopathy 5B, autosomal recessive, childhood-onset (MONDO:0957281), nemaline myopathy (MONDO:0018958)

Orphanet (1): Amish nemaline myopathy (Orphanet:98902)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000276	Long face
HP:0000768	Pectus carinatum
HP:0001239	Wrist flexion contracture
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001337	Tremor
HP:0001533	Slender build
HP:0001761	Pes cavus
HP:0001771	Achilles tendon contracture
HP:0002015	Dysphagia
HP:0002058	Myopathic facies
HP:0002093	Respiratory insufficiency
HP:0002194	Delayed gross motor development
HP:0002421	Poor head control
HP:0002474	Expressive language delay
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002751	Kyphoscoliosis
HP:0002870	Obstructive sleep apnea
HP:0003044	Shoulder flexion contracture
HP:0003184	Decreased hip abduction
HP:0003198	Myopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_457	Height	1.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290
C538397	Nemaline myopathy 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
Doxorubicin	affects expression, decreases expression	4
methylmercuric chloride	decreases expression	3
Tretinoin	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Triclosan	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects expression	2
tetrahydrocannabivarin 9	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
acipimox	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,7-dihydroxynaphthalene	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
cannabidivarin	increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1

Cellosaurus cell lines

6 cell lines: 6 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_EH14	GM14018	Transformed cell line	Female
CVCL_EH15	GM14023	Transformed cell line	Male
CVCL_EH16	GM14025	Transformed cell line	Male
CVCL_EH17	GM14026	Transformed cell line	Female
CVCL_EH18	GM14075	Transformed cell line	Female
CVCL_EH19	GM14076	Transformed cell line	Male

Clinical trials (associated diseases)

56 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT01225614	PHASE3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
NCT00278564	PHASE1	TERMINATED	Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases
NCT06374719	Not specified	RECRUITING	WiTNNess - TNNT1 Myopathy Natural History Study
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT03728803	Not specified	COMPLETED	Inspiratory Muscle Training in Nemaline Myopathy
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06670378	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in the UK
NCT06774703	Not specified	NOT_YET_RECRUITING	Nemaline Myopathy Clinical Research Network (NM-CTRN)
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT07201636	Not specified	NOT_YET_RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Belgium
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07488806	Not specified	RECRUITING	Natural History Study for Patients With Nemaline Myopathy in Spain
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02124070	PHASE1/PHASE2	WITHDRAWN	Therapeutic Effect of Recombinant Human Growth Hormone (rhGH) on the Myopathy of Cystinosis
NCT00549029	Not specified	UNKNOWN	The Association of Genetic Polymorphisms With Statin-Induced Myopathy.
NCT00767130	Not specified	UNKNOWN	DNA Diagnostic System for Statin Safety and Efficacy
NCT00922428	Not specified	COMPLETED	PASCOE-Agil HOM-Injektopas in the Treatment of Rheumatic Disorders
NCT00937001	Not specified	ACTIVE_NOT_RECRUITING	Critical Illness Myopathy as a Cause of Debilitating ICU-Acquired Weakness
NCT00990834	Not specified	WITHDRAWN	Muscle Characteristics Associated With Statin Therapy
NCT01022450	Not specified	UNKNOWN	Study of the Causes of the Breakdown of Muscle Fibers in Hospitalized Patients
NCT01040650	Not specified	TERMINATED	Metabolic Features of Post-Myopathy Patients Associated With Statin Treatment
NCT01047163	Not specified	COMPLETED	Maintenance of Muscle Mass in Older People: the Negative Impact of Statin Therapy
NCT01270269	Not specified	COMPLETED	ACT-ICU Study: Activity and Cognitive Therapy in the Intensive Care Unit
NCT01353430	Not specified	RECRUITING	Characterization of Inclusion Body Myopathy Associated With Paget’s Disease of Bone and Frontotemporal Dementia (IBMPFD)
NCT01395563	Not specified	WITHDRAWN	Strength Training on Pancreatic Cancer
NCT01530841	Not specified	COMPLETED	Efficacy and Tolerance of AVAPS Mode in Myotonic Dystrophy
NCT01547767	Not specified	COMPLETED	Investigations Into ISCU Myopathy or Iron Sulfur Scaffold U Protein Myopathy
NCT01702987	Not specified	COMPLETED	Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS
NCT01790178	Not specified	COMPLETED	Ultrasound in Muscle Biopsy
NCT02011282	Not specified	COMPLETED	Electro-Neuro-Muscular Stimulation in ICU
NCT02104921	Not specified	COMPLETED	Innovative Ultrasound Technology in Neuromuscular Disease
NCT02118805	Not specified	COMPLETED	Innovative Measures of Speech and Swallowing Dysfunction in Neurological Disorders
NCT02235220	Not specified	UNKNOWN	Reduction of Masticatory Muscle Activity by Restoring Canine Guidance
NCT02247895	Not specified	TERMINATED	Treatment of Muscle Weakness in Critically Ill Patients
NCT02315339	Not specified	TERMINATED	European Home Mechanical Ventilation Registry
NCT02442986	Not specified	COMPLETED	Neurological Outcome in Surgical and Non-surgical Septic Patients