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…

Primary Disease Associations & Inheritance

Nemaline myopathy 5A, autosomal recessive, severe infantileMIM #605355

Nemaline myopathy 5B, autosomal recessive, childhood-onsetMIM #620386

Nemaline myopathy 5C, autosomal dominantMIM #620389

Clinical highlights

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.48

LOEUF

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in TNNT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

416 rare PASS variants

Rare truncating (LoF)

1 in 900

105 rare PASS variants

Rare synonymous (reference)

1 in 410

160 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNNT1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 1,100
South Asian	~43k	1 in 140	1 in 1,300
Remaining (unassigned)	~30k	1 in 190	1 in 1,400
European (Finnish)	~27k	1 in 630	1 in 2,900
Admixed American	~22k	1 in 200	1 in 1,500
African / African American	~21k	1 in 160	1 in 1,300
East Asian	~20k	1 in 95	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 480	≈ 1 in 11,000
Middle Eastern	~2,884	1 in 240	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 11 of 13 coding exons well covered in gnomAD exomes; exons 4, 5 marginal. Genomes: 12 of 13 (exon 5 below).? see exons ↓