TNNT1

protein-coding

troponin T1, slow skeletal type, the group of Troponin complex subunits

Gene summary

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]

MANE transcript

NM_003283.6

Inheritance

AR, AD

ClinVar variants

P:38U:124B:67

Top phenotype

Nemaline myopathy 5C, autosomal dominant; Nemaline myopathy 5A, severe infantile; Nemaline myopathy 5B, childhood-onset

gnomAD constraint

pLI —, LoF o/e 1.02

Max pathogenic AF

—

Genomic locus

chr19:55,132,698-55,149,206

External References & Databases

Ensembl (ENSG00000105048)

Transcript & Mutation Effects

hg38 • Region Span ~16.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nemaline myopathy 5B, autosomal recessive, childhood-onsetSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957281

Submitter: PanelApp Australia

nemaline myopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018958

Submitter: ClinGen

TNNT1 was first reported in relation to autosomal dominant nemaline myopathy in 2017 (Konersman CG, et al., 2017, PMID: 29178646). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. To date three missense variants, at or adjacent to the tropomyosin‐binding site 1 region, have been reported in humans occurring in three proband (PMIDs: 29178646, 34440373, 35510366) and at least 8 additional affected family members (PMIDs: 29178646, 35510366). The mechanism for disease is thought to be gain of function but has not been experimentally determined. This gene-disease relationship is supported by its biochemical function in muscle contraction, interaction with additional nemaline myopathy gene TPM2, and expression in skeletal muscle. 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 recessive nemaline myopathy 5. These have been assessed separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (loss of function versus potential gain of function), inheritance pattern (autosomal recessive versus autosomal dominant), and phenotypic variability (the missense autosomal dominant mutation results in a mild phenotype with considerable clinical heterogeneity, whereas the recessive truncating and internal deletion mutations with loss of function are associated with severe, early‐onset phenotypes). Therefore, we have split curations for the disease entities, autosomal dominant nemaline myopathy and autosomal recessive nemaline myopathy 5. This gene-disease pair was originally approved by the ClinGen Congenital Myopathies Working Group on 06/22/20 (SOP Version 7). It was reevaluated on 03/19/2025. Two additional cases were identified (PMIDs: 34440373, 35510366) and the classification remained at Limited (SOP Version 11).

nemaline myopathy 5C, autosomal dominantLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957284

Submitter: Ambry Genetics

nemaline myopathy 5SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011539

Submitter: Orphanet

nemaline myopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018958

Submitter: PanelApp Australia

nemaline myopathy 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011539

Submitter: Labcorp Genetics (formerly Invitae)

nemaline myopathy 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011539

Submitter: ClinGen

TNNT1 was first reported in relation to autosomal recessive nemaline myopathy 5 in 2000 (Johnston JJ, et al., 2000, PMID: 10952871). At least eight unique variants (nonsense, frameshift, and deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 6 probands in 6 publications (PMIDs: 26296490, 31604653, 10952871, 25430424, 24689076, 29792937). Variants in this gene segregated with disease in 16 additional family members. The mechanism for disease is homozygous, or compound heterozygous, loss of function. This gene-disease relationship is supported by its biochemical function in muscle contraction, expression in skeletal muscle, functional alteration in non-patient cells, and models in both zebrafish and mouse. In summary, TNNT1 is definitively associated with autosomal recessive nemaline myopathy 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in autosomal dominant nemaline myopathy. These have been assessed separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (loss of function versus potential gain of function), inheritance pattern (autosomal recessive versus autosomal dominant), and phenotypic variability (the missense autosomal dominant mutation results in a mild phenotype with considerable clinical heterogeneity, whereas the recessive truncating and internal deletion mutations with loss of function are associated with severe, early‐onset phenotypes). Therefore, we have split curations for the disease entities, autosomal dominant nemaline myopathy and autosomal recessive nemaline myopathy 5.

nemaline myopathy 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011539

Submitter: Ambry Genetics

nemaline myopathy 5C, autosomal dominantLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0957284

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nemaline myopathy 5C, autosomal dominant; Nemaline myopathy 5A, severe infantile; Nemaline myopathy 5B, childhood-onsetAD/AR

Manifestation: 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: 10952871; 29178646; 29931346; 31970803; 35165004; 35510366; 35833674

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNNT1 variants in ClinVar

8 Conditions Cataloged

Nemaline myopathy 5Total: 300

not providedTotal: 82

Inborn genetic diseasesTotal: 39

not specifiedTotal: 23

TNNT1-related disorderTotal: 8

Nemaline myopathy 5B, autosomal recessive, childhood-onsetTotal: 6

Nemaline myopathy 5C, autosomal dominantTotal: 4

MyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003283.6. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	60 clinvar	2 clinvar	63
missense	3 clinvar		120 clinvar	4 clinvar	1 clinvar	128
nonsense	8 clinvar	2 clinvar				10
start loss		1 clinvar				1
frameshift	9 clinvar	3 clinvar				12
splice donor/acceptor (+/-2bp)	2 clinvar	10 clinvar	3 clinvar			15
Total	22	16	124	64	3	229

Highest pathogenic variant AF is 0.00015174306

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003283.6	RefSeq	NP_003274.3	13	MANE Select
ENST00000588981.6	Ensembl	ENSP00000467176.1	13	MANE Select
NM_001126132.3	RefSeq	NP_001119604.1	13	Standard
NM_001126133.3	RefSeq	NP_001119605.1	12	Standard

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
transition between fast and slow fiber
muscle filament sliding
slow-twitch skeletal muscle fiber contraction

Molecular Function

calcium ion binding
protein binding
tropomyosin binding
calcium-dependent ATPase activity
troponin T binding

Cellular Component

cytosol
troponin complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000588981
Coding exons: 13
Length: 16561
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.990	139	176	0.790	0.0000121	1800
Missense (PolyPhen)		54	90.956	0.5937		824
Synonymous	-0.324	66	62.7	1.05	0.00000385	486
Loss of Function	-0.0806	20	19.6	1.02	8.48e-7	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00018	0.00017	rare
South Asian	0.00036	0.00036	rare
Other	0	0.0	absent

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: Nemaline myopathy 5 (NEM5) [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. Nemaline myopathy type 5 is a severe and progressive form common among Old Order Amish. 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. {ECO:0000269|PubMed:10952871}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.209

Intolerance Scores

LoFtool: 0.132
RVIS EVS: -0.1
RVIS percentile EVS: 46.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.503

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium