TNNT3

Summary

TNNT3 (troponin T3, fast skeletal type, HGNC:11950) is a protein-coding gene on chromosome 11p15.5, encoding Troponin T, fast skeletal muscle (P45378). Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

The binding of Ca(2+) to the trimeric troponin complex initiates the process of muscle contraction. Increased Ca(2+) concentrations produce a conformational change in the troponin complex that is transmitted to tropomyosin dimers situated along actin filaments. The altered conformation permits increased interaction between a myosin head and an actin filament which, ultimately, produces a muscle contraction. The troponin complex has protein subunits C, I, and T. Subunit C binds Ca(2+) and subunit I binds to actin and inhibits actin-myosin interaction. Subunit T binds the troponin complex to the tropomyosin complex and is also required for Ca(2+)-mediated activation of actomyosin ATPase activity. There are 3 different troponin T genes that encode tissue-specific isoforms of subunit T for fast skeletal-, slow skeletal-, and cardiac-muscle. This gene encodes fast skeletal troponin T protein; also known as troponin T type 3. Alternative splicing results in multiple transcript variants encoding additional distinct troponin T type 3 isoforms. A developmentally regulated switch between fetal/neonatal and adult troponin T type 3 isoforms occurs. Additional splice variants have been described but their biological validity has not been established. Mutations in this gene may cause distal arthrogryposis multiplex congenita type 2B (DA2B).

Source: NCBI Gene 7140 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal arthrogryposis type 2B1 (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 312 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• MANE Select transcript: NM_006757

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11950
Approved symbol	TNNT3
Name	troponin T3, fast skeletal type
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	AMCD2B, DA2B, FSSV, DKFZp779M2348
Ensembl gene	ENSG00000130595
Ensembl biotype	protein_coding
OMIM	600692
Entrez	7140

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 72 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000278317, ENST00000344578, ENST00000381557, ENST00000381558, ENST00000381563, ENST00000381579, ENST00000381589, ENST00000397301, ENST00000397304, ENST00000446240, ENST00000453458, ENST00000473100, ENST00000492075, ENST00000493234, ENST00000639560, ENST00000641119, ENST00000641225, ENST00000641787, ENST00000706488, ENST00000943880, ENST00000943881, ENST00000943882, ENST00000943883, ENST00000943884, ENST00000943885, ENST00000943886, ENST00000943887, ENST00000943888, ENST00000943889, ENST00000943890, ENST00000943891, ENST00000943892, ENST00000943893, ENST00000943894, ENST00000943895, ENST00000943896, ENST00000943897, ENST00000943898, ENST00000943899, ENST00000943900, ENST00000943901, ENST00000943902, ENST00000943903, ENST00000943904, ENST00000943905, ENST00000943906, ENST00000943907, ENST00000943908, ENST00000943909, ENST00000943910, ENST00000943911, ENST00000943912, ENST00000943913, ENST00000943914, ENST00000943915, ENST00000943916, ENST00000943917, ENST00000943918, ENST00000943919, ENST00000943920, ENST00000943921, ENST00000943922, ENST00000943923, ENST00000943924, ENST00000943925, ENST00000943926, ENST00000943927, ENST00000943928, ENST00000943929, ENST00000943930, ENST00000943931, ENST00000943932, ENST00000943933, ENST00000943934, ENST00000943935, ENST00000943936

RefSeq mRNA: 17 — MANE Select: NM_006757 NM_001042780, NM_001042781, NM_001042782, NM_001297646, NM_001363561, NM_001367842, NM_001367843, NM_001367844, NM_001367845, NM_001367846, NM_001367847, NM_001367848, NM_001367849, NM_001367850, NM_001367851, NM_001367852, NM_006757

CCDS: CCDS41594, CCDS41595, CCDS41596, CCDS7727, CCDS86164, CCDS91403, CCDS91406

Canonical transcript exons

ENST00000278317 — 16 exons

Exon	Start	End
ENSE00001057465	1936963	1937003
ENSE00001289607	1929120	1929143
ENSE00001402678	1922857	1922891
ENSE00001649582	1923555	1923572
ENSE00001721721	1923048	1923061
ENSE00001741603	1925099	1925116
ENSE00001919217	1919703	1919762
ENSE00003485053	1932469	1932514
ENSE00003519409	1934332	1934445
ENSE00003524302	1926695	1926709
ENSE00003539797	1933721	1933837
ENSE00003560178	1934546	1934655
ENSE00003596363	1929810	1929828
ENSE00003606462	1933931	1934008
ENSE00003786295	1934829	1934919
ENSE00003845541	1938438	1938702

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.90.

FANTOM5 (CAGE): breadth broad, TPM avg 65.3068 / max 13753.0778, expressed in 312 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112551	63.1263	235
112571	0.5279	36
112556	0.3647	90
112558	0.3448	54
112550	0.1973	43
112559	0.1298	31
112575	0.1286	27
112579	0.0960	13
112573	0.0938	14
112576	0.0805	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.90	gold quality
skeletal muscle tissue	UBERON:0001134	99.89	gold quality
gastrocnemius	UBERON:0001388	99.88	gold quality
muscle organ	UBERON:0001630	99.62	gold quality
skeletal muscle organ	UBERON:0014892	99.62	gold quality
muscle of leg	UBERON:0001383	99.61	gold quality
apex of heart	UBERON:0002098	98.97	gold quality
heart left ventricle	UBERON:0002084	96.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.04	gold quality
placenta	UBERON:0001987	95.42	gold quality
right uterine tube	UBERON:0001302	95.35	gold quality
right atrium auricular region	UBERON:0006631	94.50	gold quality
heart	UBERON:0000948	93.71	gold quality
muscle tissue	UBERON:0002385	92.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.46	gold quality
calcaneal tendon	UBERON:0003701	91.27	gold quality
adipose tissue	UBERON:0001013	91.04	gold quality
omental fat pad	UBERON:0010414	90.53	gold quality
fallopian tube	UBERON:0003889	89.72	gold quality
left uterine tube	UBERON:0001303	89.43	gold quality
urinary bladder	UBERON:0001255	89.41	gold quality
ectocervix	UBERON:0012249	89.36	gold quality
vagina	UBERON:0000996	87.91	gold quality
blood	UBERON:0000178	86.52	gold quality
endocervix	UBERON:0000458	85.36	gold quality
minor salivary gland	UBERON:0001830	85.25	gold quality
skin of abdomen	UBERON:0001416	85.16	gold quality
body of uterus	UBERON:0009853	85.16	gold quality
thoracic mammary gland	UBERON:0005200	84.80	gold quality
nerve	UBERON:0001021	84.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-5	yes	769.53
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting TNNT3, 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-1184	99.99	68.19	1458
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-6796-5P	95.37	66.08	1120

Literature-anchored findings (GeneRIF, showing 9)

• These results indicate that the f peptide confers an inhibitory effect on the biological function of fast skeletal troponin T and this can be correlated with changes in the Ca2+ regulation associated with development in fast skeletal muscle. (PMID:16081096)
• Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. (PMID:19142688)
• Myotonic dystrophy type 2 muscles exhibited a higher degree of alternative splicing dysregulation for fast TnT transcripts when compared to myotonic dystrophy type 1 muscles. (PMID:19326042)
• TNNT3 and LDB3 showed abnormal splicing and appeared more pronounced in myotonic dystrophies type 2 relative to myotonic dystrophies type 1. (PMID:20066428)
• Data show that a missense mutation at nucleotide position 187 in exon 9 of the TNNT3 gene was identified in all affected individuals in the family. (PMID:21402185)
• 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)
• The presence of the p.(Arg63His) missense mutation at position 63 of TNNT3 was confirmed through direct cycle sequencing of genomic DNA in six affected South African family members for whom DNA had been archived. (PMID:26915936)
• The TnT3 appears to contribute to age-related sarcopenia and possibly other age-related deficiencies such as muscle insulin resistance and beta cell dysfunction by interacting with TnT3-binding sequences in the promoter area of p53-related genes, among others, and consequently modulating the transcriptional regulation of these target genes. (PMID:29596868)
• The distal arthrogryposis-linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3. (PMID:34766372)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnnt3a	ENSDARG00000030270
danio_rerio	tnnt3b	ENSDARG00000068457
mus_musculus	Tnnt3	ENSMUSG00000061723
rattus_norvegicus	Tnnt3	ENSRNOG00000020332
drosophila_melanogaster	up	FBGN0004169
caenorhabditis_elegans		WBGENE00006588

Paralogs (2): TNNT1 (ENSG00000105048), TNNT2 (ENSG00000118194)

Protein

Protein identifiers

Troponin T, fast skeletal muscle — P45378 (reviewed: P45378)

Alternative names: Beta-TnTF, Fast skeletal muscle troponin T

All UniProt accessions (7): P45378, A0A286YFB1, A0A9L9PY19, C9JCA5, C9JZN9, F8WA37, H9KVA2

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.

Tissue specificity. In fetal and adult fast skeletal muscles, with a higher level expression in fetal than in adult muscle.

Disease relevance. Arthrogryposis, distal, 2B2 (DA2B2) [MIM:618435] A form of distal arthrogryposis, a disease characterized by congenital joint contractures that mainly involve two or more distal parts of the limbs, in the absence of a primary neurological or muscle disease. Distal arthrogryposis type 2 is characterized by contractures of the hands and feet, and a distinctive face characterized by prominent nasolabial folds, small mouth and downslanting palpebral fissures. DA2B2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Minor isoform detected in approximately 1% of cDNA clones.

Similarity. Belongs to the troponin T family.

Isoforms (7)

UniProt ID	Names	Canonical?
P45378-1	1, Tnt1	yes
P45378-2	2, Tnt3
P45378-3	3, Tnt1f
P45378-4	4, Tnt3f
P45378-5	5, Tnt3f*
P45378-6	6
P45378-7	7

RefSeq proteins (17): NP_001036245, NP_001036246, NP_001036247, NP_001284575, NP_001350490, NP_001354771, NP_001354772, NP_001354773, NP_001354774, NP_001354775, NP_001354776, NP_001354777, NP_001354778, NP_001354779, NP_001354780, NP_001354781, NP_006748* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00992

UniProt features (24 total): modified residue 6, splice variant 5, compositionally biased region 5, region of interest 3, sequence variant 2, initiator methionine 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45378-F1	77.99	0.46

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 (6): 2, 2, 88, 159, 166, 167

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction

MSigDB gene sets: 237 (showing top): MYOGENIN_Q6, AREB6_03, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, HUMMERICH_BENIGN_SKIN_TUMOR_DN, HUMMERICH_MALIGNANT_SKIN_TUMOR_DN, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, MODULE_329, GOBP_SARCOMERE_ORGANIZATION, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_SKELETAL_MUSCLE_CONTRACTION, CAGCTG_AP4_Q5, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION

GO Biological Process (7): skeletal muscle contraction (GO:0003009), regulation of striated muscle contraction (GO:0006942), regulation of ATP-dependent activity (GO:0043462), sarcomere organization (GO:0045214), positive regulation of calcium-dependent ATPase activity (GO:1903612), regulation of muscle contraction (GO:0006937), striated muscle contraction (GO:0006941)

GO Molecular Function (5): tropomyosin binding (GO:0005523), troponin C binding (GO:0030172), troponin I binding (GO:0031013), calcium-dependent protein binding (GO:0048306), actin binding (GO:0003779)

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
striated muscle contraction	2
muscle contraction	2
musculoskeletal movement	1
regulation of muscle contraction	1
regulation of molecular function	1
ATP-dependent activity	1
myofibril assembly	1
actomyosin structure organization	1
calcium-dependent ATPase activity	1
positive regulation of ATP-dependent activity	1
regulation of muscle system process	1
calcium ion binding	1
protein binding	1
cytoplasm	1
cellular anatomical structure	1
striated muscle thin filament	1
protein-containing complex	1

Protein interactions and networks

STRING

1146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNNT3	TNNI2	P48788	988
TNNT3	TNNI1	P19237	935
TNNT3	TPM2	P06468	897
TNNT3	MYH3	P11055	886
TNNT3	TNNC2	P02585	828
TNNT3	ACTN3	Q08043	826
TNNT3	ACTA1	P02568	791
TNNT3	CLCN1	P35523	785
TNNT3	TNNC1	P02590	784
TNNT3	MTMR1	Q13613	774
TNNT3	FRG1	Q14331	763
TNNT3	MBNL1	Q9NR56	752
TNNT3	LDB3	O75112	748
TNNT3	ACTN2	P35609	746
TNNT3	FRG2	Q64ET8	739

IntAct

19 interactions, top by confidence:

A	B	Type	Score
H3-4	TNNT3	psi-mi:“MI:0915”(physical association)	0.400
NUDT3	TNNT3	psi-mi:“MI:0915”(physical association)	0.370
RSPH6A	ATP2A1	psi-mi:“MI:0914”(association)	0.350
PGPEP1	TNNT3	psi-mi:“MI:0914”(association)	0.350
TNNT3	MAEA	psi-mi:“MI:0914”(association)	0.350
TNFSF14	HAX1	psi-mi:“MI:0914”(association)	0.350
LATS1	ATP2A1	psi-mi:“MI:0914”(association)	0.350
TSPAN33	ATP2A1	psi-mi:“MI:0914”(association)	0.350
FGFBP2	RAB4A	psi-mi:“MI:0914”(association)	0.350
MFGE8	MYH7B	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
TTC4	MYH7B	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TNNT3	CLIP4	psi-mi:“MI:0915”(physical association)	0.000
TNNT3	TULP3	psi-mi:“MI:0915”(physical association)	0.000
TNNT3	WASL	psi-mi:“MI:0915”(physical association)	0.000
TNNT3	HAP1	psi-mi:“MI:0915”(physical association)	0.000
SNUPN	TNNT3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): TNNT3 (Affinity Capture-MS), TNNT3 (Two-hybrid), TNNT3 (Affinity Capture-MS), TNNT3 (Affinity Capture-MS), TNNT3 (Two-hybrid), HAP1 (Two-hybrid), HIST3H3 (Proximity Label-MS), TNNT3 (Two-hybrid), TNNT3 (Two-hybrid), TNNT3 (Two-hybrid), TNNT3 (Positive Genetic), GID4 (Affinity Capture-MS), TXLNG (Affinity Capture-MS), TNNT3 (Affinity Capture-MS), ARMC8 (Affinity Capture-MS)

ESM2 similar proteins: A5JSS4, B1MTI8, O88892, P02641, P06398, P09739, P0C0A9, P12620, P45378, P84101, P84102, Q05310, Q0UVD1, Q148I0, Q1E554, Q28HN4, Q28IN9, Q2KIT1, Q2TBR9, Q2TBV6, Q32P76, Q3E7B7, Q4I5Z5, Q5R5J3, Q5R6N0, Q5R7C4, Q5R8X8, Q5REM2, Q5ZHK9, Q68EY7, Q6DD17, Q6GNG8, Q6NVR5, Q6PHE8, Q75NG9, Q7SDA6, Q7ZY35, Q8MKI3, Q8NHG7, Q8R1F0

Diamond homologs: O88346, P02641, P02642, P06398, P09739, P09741, P12620, P13789, P13805, P19351, P45378, P45379, P50751, P50752, P50753, Q75NG9, Q75ZZ6, Q7TNB2, Q8MKH6, Q8MKI3, Q9QZ47, Q9XZ71, Q27371

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	TNNT3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	132
Likely benign	95
Benign	61

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1028551	NM_006757.4(TNNT3):c.723-2A>G	Pathogenic
980415	GRCh37/hg19 11p15.5(chr11:1436158-2321134)x3	Pathogenic
1172549	NM_006757.4(TNNT3):c.187C>A (p.Arg63Ser)	Likely pathogenic

SpliceAI

2630 predictions. Top by Δscore:

Variant	Effect	Δscore
11:1925243:C:CA	acceptor_gain	1.0000
11:1925244:G:A	acceptor_gain	1.0000
11:1926348:C:A	acceptor_gain	1.0000
11:1926351:A:AG	acceptor_gain	1.0000
11:1926351:AC:A	acceptor_gain	1.0000
11:1926352:C:CA	acceptor_gain	1.0000
11:1926355:A:AG	acceptor_gain	1.0000
11:1926661:C:CA	acceptor_gain	1.0000
11:1926670:T:A	acceptor_gain	1.0000
11:1929768:ACGCT:A	acceptor_gain	1.0000
11:1933716:CACA:C	acceptor_loss	1.0000
11:1933718:CA:C	acceptor_loss	1.0000
11:1933719:A:AG	acceptor_gain	1.0000
11:1933719:AG:A	acceptor_gain	1.0000
11:1933720:G:GT	acceptor_gain	1.0000
11:1933720:GG:G	acceptor_gain	1.0000
11:1933720:GGA:G	acceptor_gain	1.0000
11:1933720:GGAC:G	acceptor_gain	1.0000
11:1933720:GGACA:G	acceptor_gain	1.0000
11:1933808:G:GT	donor_gain	1.0000
11:1933833:GAATC:G	donor_gain	1.0000
11:1933835:ATC:A	donor_gain	1.0000
11:1933836:TC:T	donor_gain	1.0000
11:1933837:CG:C	donor_loss	1.0000
11:1933838:G:GG	donor_gain	1.0000
11:1933838:G:T	donor_loss	1.0000
11:1933839:T:G	donor_loss	1.0000
11:1933987:G:GT	donor_gain	1.0000
11:1934072:GGGGC:G	donor_gain	1.0000
11:1934329:CAGGA:C	acceptor_loss	1.0000

AlphaMissense

1730 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:1933736:C:A	R74S	1.000
11:1933761:T:C	L82P	1.000
11:1933770:T:C	L85P	1.000
11:1933781:C:G	H89D	1.000
11:1932509:T:C	F67L	0.999
11:1932510:T:G	F67C	0.999
11:1932511:C:A	F67L	0.999
11:1932511:C:G	F67L	0.999
11:1933737:G:C	R74P	0.999
11:1933747:A:C	K77N	0.999
11:1933747:A:T	K77N	0.999
11:1933752:T:C	L79P	0.999
11:1933761:T:A	L82H	0.999
11:1933773:T:A	I86N	0.999
11:1933783:C:A	H89Q	0.999
11:1933783:C:G	H89Q	0.999
11:1933784:T:C	F90L	0.999
11:1933786:T:A	F90L	0.999
11:1933786:T:G	F90L	0.999
11:1933794:G:C	R93P	0.999
11:1933824:T:C	L103P	0.999
11:1933937:C:A	R110S	0.999
11:1934836:G:C	A211P	0.999
11:1932510:T:C	F67S	0.998
11:1933745:A:G	K77E	0.998
11:1933746:A:T	K77I	0.998
11:1933773:T:G	I86S	0.998
11:1933782:A:C	H89P	0.998
11:1933785:T:C	F90S	0.998
11:1933938:G:C	R110P	0.998

dbSNP variants (sampled 300 via entrez): RS1000472710 (11:1922784 A>G,T), RS1000486925 (11:1933352 C>T), RS1000488078 (11:1930048 G>A), RS1000593969 (11:1918200 G>T), RS1000608961 (11:1937949 C>T), RS1000638721 (11:1938160 T>A), RS1000789018 (11:1933002 G>A), RS1000835287 (11:1929190 C>A), RS1000836466 (11:1931495 G>A), RS1000966125 (11:1917937 A>G), RS1001028434 (11:1918353 C>A,T), RS1001038422 (11:1925082 G>A,C), RS1001047609 (11:1922614 C>A), RS1001128375 (11:1920792 G>A), RS1001472532 (11:1923769 CTTAA>C)

Disease associations

OMIM: gene MIM:600692 | disease phenotypes: MIM:618435, MIM:601680, MIM:256030, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis, distal, type 2B2	Strong	Autosomal dominant
distal arthrogryposis type 2B1	Strong	Autosomal dominant
congenital myopathy	Strong	Autosomal recessive
nemaline myopathy	Moderate	Autosomal recessive
digitotalar dysmorphism	Supportive	Autosomal dominant
Sheldon-hall syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nemaline myopathy	Limited	AR

Mondo (6): arthrogryposis, distal, type 2B2 (MONDO:0032750), distal arthrogryposis type 2B1 (MONDO:0020820), nemaline myopathy (MONDO:0018958), Sheldon-hall syndrome (MONDO:0011128), congenital myopathy (MONDO:0019952), digitotalar dysmorphism (MONDO:0015240)

Orphanet (3): Sheldon-Hall syndrome (Orphanet:1147), Nemaline myopathy (Orphanet:607), Congenital myopathy (Orphanet:97245)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0001156	Brachydactyly
HP:0001181	Adducted thumb
HP:0001182	Tapered finger
HP:0001387	Joint stiffness
HP:0001762	Talipes equinovarus
HP:0001772	Talipes equinovalgus
HP:0001831	Short toe
HP:0001838	Rocker bottom foot
HP:0001840	Metatarsus adductus
HP:0001852	Sandal gap
HP:0001883	Talipes
HP:0002650	Scoliosis
HP:0002827	Hip dislocation
HP:0003049	Ulnar deviation of the wrist
HP:0003272	Abnormal hip bone morphology
HP:0003422	Vertebral segmentation defect
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0006501	Aplasia/Hypoplasia of the radius
HP:0007598	Bilateral single transverse palmar creases

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002112_1	Celiac disease	7.000000e-06
GCST002667_7	Mammographic density (dense area)	1.000000e-10
GCST006168_34	Pulse pressure x alcohol consumption interaction (2df test)	7.000000e-31
GCST006187_29	Diastolic blood pressure (cigarette smoking interaction)	3.000000e-23
GCST006188_8	Systolic blood pressure (cigarette smoking interaction)	3.000000e-40
GCST006190_36	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-10
GCST006190_89	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	5.000000e-11
GCST006192_23	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-19
GCST006192_9	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-20
GCST006193_20	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	9.000000e-10
GCST006193_60	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-10
GCST006195_28	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-19
GCST006195_50	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-20
GCST006231_44	Mean arterial pressure	3.000000e-08
GCST006258_41	Diastolic blood pressure	4.000000e-13
GCST006259_2	Systolic blood pressure	2.000000e-14
GCST007706_111	Mean arterial pressure	2.000000e-07
GCST007707_38	Hypertension	7.000000e-08
GCST90000025_188	Appendicular lean mass	5.000000e-15

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0004329	alcohol drinking
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017696	Myopathies, Nemaline	C05.651.575.290; C10.668.491.550.290
C565097	Digitotalar Dysmorphism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3831282 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	2
Air Pollutants	increases abundance, increases expression, affects expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
tebuconazole	decreases expression	1
bisphenol S	decreases expression	1
incobotulinumtoxinA	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases expression, increases abundance	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02035501	PHASE2	UNKNOWN	Treatment of TNNT1-Myopathy With L-Tyrosine.
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
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05419245	Not specified	UNKNOWN	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT02020187	Not specified	COMPLETED	Aerobic Training in Patients With Congenital Myopathies
NCT03018184	Not specified	COMPLETED	Contractile Cross Sectional Areas and Muscle Strength in Patients With Congenital Myopathies
NCT04733976	Not specified	COMPLETED	Bullying in Youth With Muscular Dystrophy and Congenital Myopathies
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
NCT07138963	Not specified	RECRUITING	Phenotype - Genotype Correlation in a Sample of Egyptian Patients With Congenital Myopathies and Congenital Muscular Dystrophies
NCT07415837	Not specified	RECRUITING	Evaluation of the Role of miR-1 in the Pathogenesis and as a Biomarker in Muscular Dystrophies and Congenital Myopathies
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07580365	Not specified	NOT_YET_RECRUITING	VirtualPark_Pediatric