TMC1

Summary

TMC1 (transmembrane channel like 1, HGNC:16513) is a protein-coding gene on chromosome 9q21.13, encoding Transmembrane channel-like protein 1 (Q8TDI8). Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.

This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness.

Source: NCBI Gene 117531 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 914 total — 110 pathogenic, 59 likely-pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_138691

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16513
Approved symbol	TMC1
Name	transmembrane channel like 1
Location	9q21.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165091
Ensembl biotype	protein_coding
OMIM	606706
Entrez	117531

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 6 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000297784, ENST00000340019, ENST00000469455, ENST00000486417, ENST00000492418, ENST00000497073, ENST00000643676, ENST00000644967, ENST00000645053, ENST00000645208, ENST00000645773, ENST00000645787, ENST00000646244, ENST00000646619, ENST00000650689, ENST00000651183, ENST00000651743

RefSeq mRNA: 1 — MANE Select: NM_138691 NM_138691

CCDS: CCDS6643

Canonical transcript exons

ENST00000297784 — 24 exons

Exon	Start	End
ENSE00000000306	72835951	72838297
ENSE00001090228	72788339	72788483
ENSE00001090229	72772413	72772555
ENSE00001090233	72791886	72792065
ENSE00001161428	72789123	72789317
ENSE00001161440	72754786	72754884
ENSE00001161446	72751850	72751956
ENSE00001161454	72742444	72742525
ENSE00001161460	72740119	72740209
ENSE00001161467	72700518	72700643
ENSE00001161472	72694543	72694714
ENSE00001161477	72688709	72688756
ENSE00001433731	72627921	72628063
ENSE00001472218	72616368	72616477
ENSE00001748113	72577902	72578023
ENSE00003514977	72826869	72826994
ENSE00003524143	72792191	72792352
ENSE00003537552	72805382	72805510
ENSE00003541879	72830451	72830529
ENSE00003566434	72816143	72816210
ENSE00003642255	72648597	72648664
ENSE00003650588	72830631	72830682
ENSE00003658540	72820842	72821081
ENSE00003900817	72521608	72521913

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 81.88.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.88	gold quality
buccal mucosa cell	CL:0002336	80.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.95	gold quality
lower esophagus mucosa	UBERON:0035834	77.32	gold quality
sural nerve	UBERON:0015488	74.36	gold quality
esophagus mucosa	UBERON:0002469	69.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	64.62	gold quality
monocyte	CL:0000576	63.00	gold quality
spinal cord	UBERON:0002240	62.41	gold quality
right uterine tube	UBERON:0001302	61.39	gold quality
leukocyte	CL:0000738	60.61	gold quality
stromal cell of endometrium	CL:0002255	59.32	gold quality
anterior cingulate cortex	UBERON:0009835	58.44	gold quality
gastrocnemius	UBERON:0001388	58.43	gold quality
testis	UBERON:0000473	58.31	gold quality
amygdala	UBERON:0001876	58.15	gold quality
muscle of leg	UBERON:0001383	57.72	gold quality
ectocervix	UBERON:0012249	57.65	gold quality
left testis	UBERON:0004533	57.52	gold quality
urinary bladder	UBERON:0001255	57.28	gold quality
esophagus	UBERON:0001043	57.12	gold quality
nucleus accumbens	UBERON:0001882	57.12	gold quality
tendon of biceps brachii	UBERON:0008188	56.94	gold quality
right testis	UBERON:0004534	56.84	gold quality
substantia nigra	UBERON:0002038	56.77	gold quality
prefrontal cortex	UBERON:0000451	56.73	gold quality
uterine cervix	UBERON:0000002	55.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	55.81	gold quality
putamen	UBERON:0001874	55.72	gold quality
hypothalamus	UBERON:0001898	55.56	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.59
E-GEOD-98556	no	52.06
E-ENAD-27	no	4.27

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX1

miRNA regulators (miRDB)

29 targeting TMC1, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-197-5P	97.23	68.10	596
HSA-MIR-4486	96.96	60.61	931
HSA-MIR-1287-5P	96.80	65.30	743
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-4435	95.90	65.47	1201

Literature-anchored findings (GeneRIF, showing 40)

• role of mutations causing dominant and recessive deafness (PMID:11850618)
• TMC1 mutations account for at least 6% (4/65) of ARNSHL in GJB2-negative Turkish families from the northeast and east of Turkey. (PMID:16287143)
• 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. (PMID:17877751)
• This study confirms that mutations in the TMC1 gene may be a common cause for autosomal recessive nonsyndromic HI. (PMID:18259073)
• linkage to DFNA36 and DFNB7/11 in 1 family with dominant and 10 families with recessive non-syndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 (PMID:18616530)
• The p.D572N mutation of TMC1 co-segregating with hearing loss in a North American family, was studied. (PMID:19180119)
• Mutaions in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss. (PMID:19187973)
• Our study shows that the p.R34X mutation in TMC1 in North African and Asian individuals arose from at least two different founders. (PMID:20373850)
• A novel dominant mutation, p.G417R, and a novel recessive mutation, p.N50KfsX26, in TMC1 in a large Iranian DFNA36 family (Family L1754 ) and a consanguineous Iranian DFNB7/11 family (Family L787), respectively, were identified. (PMID:20447146)
• DFNB7/11 is a common form of genetic hearing loss in Iran, because this population is the source of 6 of the 29 TMC1 mutations reported worldwide (PMID:21250555)
• A novel homozygous A-to-G change in the TMC1 gene was detected near the splice donor site of intron 19 (c.1763+3A–>G) segregating with the hearing loss in a Dutch family (PMID:21252500)
• A single founder mutation, c.100C>T (p.Arg34X) that dominates the TMC1 mutation spectrum is not a significant cause of deafness in British Aasians. (PMID:22288896)
• DNA sequencing of all coding and non-coding exons and intron boundaries of the TMC1 gene identified c.-258A>C mutation in non-coding exon 3 only in individuals from two ethnically related Iranian with hearing loss. (PMID:23523375)
• hearing loss in this family was caused by novel compound heterozygous mutations in TMC1 (PMID:23690975)
• Description of the spectrum of mutations in TMC1 in 374 families with autosomal recessive, non-syndromic hearing loss from India. (PMID:24416283)
• TMC1 is expressed in the hair cells in inner ear. (PMID:24827932)
• TMC1 mutations disrupt hair cell mechanoelectrical transduction and are responsible for DFNA36 and DFNB7/B11. [Review Article] (PMID:24933710)
• Co-segregation of c.2030T>C mutation with hearing loss in an Iranian family and absence of this mutation in 100 Iranian controls confirms the pathogenicity of this mutation. (PMID:25423259)
• The novel compound heterozygous mutant alleles of TMC1 identified in this study were responsible for the autosomal recessive non-syndromic hearing loss in this Tibetan Chinese family. (PMID:25458163)
• one heterozygous, non-synonymous variant was detected, with the SNP causing an amino acid substitution in TMC1 in a Polish family with hearing impairment (PMID:25560804)
• TMC1 has been identified as the causative gene in a six-generation Chinese family with autosomal dominant hearing loss. (PMID:26079994)
• The first mutation in the TMC1 gene in the Moroccan population causing non-syndromic hearing loss. (PMID:26226225)
• a novel TMC1 mutation in exon 20, c.1979C>T, p.P660L, which segregated with prelingual autosomal recessive sensorineural hearing loss, was found. (PMID:26822030)
• there is hypo-functional TMC1 mechanotransduction channel activity and other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss. (PMID:26879195)
• But the great majority of evidence is consistent with these TMCs as pore-forming subunits of the long-sought hair-cell transduction channel. [review] (PMID:27798174)
• Pathogenic variations in the TMC1 gene (encoding the transmembrane channel-like protein 1) are found in more than a third of hearing-impaired Jewish patients of Moroccan ancestry. (PMID:28821934)
• the identification of a previously identified c.100C>T mutation, and a novel homozygous mutation, c.1283C>A in TMC1, in this study supports TMC1 gene as one of the second-tier hearing loss genes, after GJB2 in India. Testing for TMC1 may be considered in all GJB2-negative nonsyndromic hearing loss cases (PMID:28862181)
• two novel mutations in the WHRN and TMC1 genes are responsible for founder effects of hereditary hemochromatosis, Wilson s disease, the long QT syndrome and autosomal recessive deafness in a Swedish pedigree (PMID:29270100)
• the whole exome sequencing (WES) in this family revealed two homozygous variants in EVC2 (c.30dupC; p.Thr11Hisfs*45) and TMC1 (c.1696-1G>A) genes. In family B, WES revealed novel compound heterozygous variants (p.Ser307Pro, c.2894+3A>G) in the EVC gene. (PMID:29321360)
• Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764-4C>A, c.2073G>A[p.K691K]) were found. Four novel variants were detected in this study; compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. (PMID:29533536)
• Novel TMC1 mutation 773G>A was identified in a family with nonsyndromic hearing loss. (PMID:29692870)
• We suggest that KCNQ1, expression of which is not thought to overlap with TMC1 in hair cells, is a proxy partner bearing structural elements or a sequence motif reminiscent of a true in vivo TMC1 hair cell partner. (PMID:30613966)
• Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL in a large family. The novel nonsense TMC1 variant meets the criteria of being pathogenic according to the ACMGAMP variant interpretation guideline. (PMID:31176026)
• Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population. (PMID:31854501)
• Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families. (PMID:32802042)
• Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. (PMID:33168709)
• Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss. (PMID:33205915)
• New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells. (PMID:33824189)
• Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss. (PMID:34523024)
• A novel splicing variant in the TMC1 gene causes non-syndromic hearing loss in a Chinese family. (PMID:35089886)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmc1	ENSDARG00000056386
mus_musculus	Tmc1	ENSMUSG00000024749
rattus_norvegicus	Tmc1	ENSRNOG00000051262
drosophila_melanogaster	Tmc	FBGN0267796

Paralogs (7): TMC5 (ENSG00000103534), TMC6 (ENSG00000141524), TMC2 (ENSG00000149488), TMC4 (ENSG00000167608), TMC8 (ENSG00000167895), TMC7 (ENSG00000170537), TMC3 (ENSG00000188869)

Protein

Protein identifiers

Transmembrane channel-like protein 1 — Q8TDI8 (reviewed: Q8TDI8)

Alternative names: Transmembrane cochlear-expressed protein 1

All UniProt accessions (7): A0A2R8Y434, A0A2R8YDA3, A0A2R8YDJ2, A0A2R8YDK2, A0A2R8YGM2, A0A494C0T8, Q8TDI8

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system. The MET complex is composed of two dimeric pore-forming ion-conducting transmembrane TMC (TMC1 or TMC2) subunits, and aided by several auxiliary proteins including LHFPL5, TMIE, CIB2/3 and TOMT, and the tip-link PCDH15. MET channel is activated by tension in the tip-link extending from the side wall of one stereocilium to the tip of the adjacent shorter stereocilium, where the channel is located. TMC1 MET channel is highly permeable to calcium and likely transports monovalent cations. Also involved in vestibular hair cells transduction current.

Subunit / interactions. Forms the MET channel complosed of TMC dimer (TMC1 or TMC2), TMIE, TOMT, CIB (CIB2 or CIB3), LHFPL5 and PDH15. The interaction of TMC1 and TMC2 with TOMT is required for the transportation of TMC1/2 into the stereocilia of hair cells. Interacts (via N-terminus) with both isoforms CD1 and CD3 of PCDH15. Can form a heterodimer with TMC2, TMC5 or TMC7.

Subcellular location. Cell membrane.

Tissue specificity. Detected in fetal cochlea, and at low levels in placenta and testis.

Disease relevance. Deafness, autosomal dominant, 36 (DFNA36) [MIM:606705] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA36 is a bilateral hearing loss, and begins at 5-10 years of age. It progresses to profound deafness within 10-15 years. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 7 (DFNB7) [MIM:600974] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. TMC1 is structurally similar to TMEM16 channel and may include ten transmembrane (TM) domains with the ion-conducting pore placed between TM4 and TM7.

Similarity. Belongs to the TMC family.

RefSeq proteins (1): NP_619636* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012496	TMC_dom	Domain
IPR038900	TMC	Family

Pfam: PF07810

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (41 total): topological domain 11, transmembrane region 10, modified residue 5, sequence variant 5, helix 4, compositionally biased region 3, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8XOQ	X-RAY DIFFRACTION	2.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDI8-F1	76.96	0.12

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 (5): 37, 45, 128, 314, 400

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 117 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_REFLEX, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EAR_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_AUDITORY_RECEPTOR_CELL_DEVELOPMENT, GOBP_MECHANORECEPTOR_DIFFERENTIATION

GO Biological Process (8): detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), vestibular reflex (GO:0060005), auditory receptor cell development (GO:0060117), regulation of calcium ion transmembrane transport (GO:1903169), monoatomic ion transport (GO:0006811), sensory perception of sound (GO:0007605), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (3): voltage-gated calcium channel activity (GO:0005245), calcium channel activity (GO:0005262), mechanosensitive monoatomic ion channel activity (GO:0008381)

GO Cellular Component (5): external side of plasma membrane (GO:0009897), stereocilium (GO:0032420), stereocilium tip (GO:0032426), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
reflex	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
regulation of calcium ion transport	1
calcium ion transmembrane transport	1
regulation of monoatomic cation transmembrane transport	1
transport	1
sensory perception of mechanical stimulus	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
monoatomic ion channel activity	1
gated channel activity	1
plasma membrane	1
cell surface	1
side of membrane	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
stereocilium	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMC1	LHFPL5	Q8TAF8	995
TMC1	TMIE	Q8NEW7	978
TMC1	CIB2	O75838	906
TMC1	TMC2	Q8TDI7	890
TMC1	PCDH15	Q96QU1	885
TMC1	MYO7A	P78427	873
TMC1	MYO15A	Q9UKN7	853
TMC1	CDH23	Q9H251	834
TMC1	OTOF	Q9HC10	829
TMC1	TJP2	Q9UDY2	811
TMC1	WHRN	Q9P202	808
TMC1	SLC26A4	O43511	794
TMC1	GJB2	P29033	787
TMC1	LOXHD1	Q8IVV2	774
TMC1	TMPRSS3	P57727	770

IntAct

9 interactions, top by confidence:

A	B	Type	Score
TMC1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
TMC1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
TMC1	CIB2	psi-mi:“MI:0915”(physical association)	0.400
PTPRE	KIF1B	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): TMC1 (Affinity Capture-MS), TMC1 (Synthetic Lethality), TMC1 (Affinity Capture-MS), TMC1 (Affinity Capture-MS), TMC1 (Proximity Label-MS), HIST1H2BH (Proximity Label-MS), CIB2 (Affinity Capture-MS), RPL34 (Cross-Linking-MS (XL-MS)), TMC1 (Affinity Capture-MS), TMC1 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A2AHL1, A8DZH4, D3ZWZ9, E7FFT2, F1QFU0, F1QZE9, P48763, P50482, P86044, Q28CV2, Q32NZ6, Q3TPR7, Q3ZAS0, Q4R7U0, Q4V8U5, Q5F3F5, Q5M7W4, Q5RH73, Q5YCC5, Q5ZKN3, Q68DH5, Q6GQE1, Q6P4P2, Q6UXY8, Q7L1W4, Q7Z2W7, Q7Z402, Q7ZYA0, Q810F5, Q8BH79, Q8C428, Q8C561, Q8CB19, Q8IZK6, Q8N3S3, Q8R455, Q8R4D5, Q8R4P4, Q8R4P5

Diamond homologs: A0A0U1QT59, E7FFT2, F1QFU0, F1QZE9, Q32NZ6, Q496Z4, Q4R7U0, Q5M7W4, Q6UXY8, Q7TN58, Q7TQ65, Q7Z402, Q7Z404, Q8C428, Q8IU68, Q8R4P4, Q8R4P5, Q8TDI7, Q8TDI8, D3KZG3, Q11069, Q5YCC7, Q7TQ69, Q7Z5M5, Q7TN60, Q7Z403

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PCDH15	“up-regulates activity”	TMC1	binding
TMC1	“form complex”	“Hair cells mechanotransduction channel”	binding
CIB2	“up-regulates activity”	TMC1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	110
Likely pathogenic	59
Uncertain significance	259
Likely benign	350
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1202329	NM_138691.3(TMC1):c.332G>A (p.Trp111Ter)	Pathogenic
1213521	NM_138691.3(TMC1):c.884+1G>A	Pathogenic
1323692	NM_138691.3(TMC1):c.236+1G>T	Pathogenic
1334111	NM_138691.3(TMC1):c.1184del (p.Gln395fs)	Pathogenic
1452909	NM_138691.3(TMC1):c.2012dup (p.Asn671fs)	Pathogenic
1460127	NC_000009.11:g.(?75231331)(75387491_?)del	Pathogenic
178942	NM_138691.3(TMC1):c.22del (p.Ile8fs)	Pathogenic
179431	NM_138691.3(TMC1):c.215_219dup (p.Arg74fs)	Pathogenic
1799540	NM_138691.3(TMC1):c.1250G>A (p.Gly417Glu)	Pathogenic
1810252	NM_138691.3(TMC1):c.846dup (p.Met283fs)	Pathogenic
183668	NM_138691.3(TMC1):c.1253T>A (p.Met418Lys)	Pathogenic
2136777	NM_138691.3(TMC1):c.458G>A (p.Trp153Ter)	Pathogenic
228405	NM_138691.3(TMC1):c.1236del (p.Met413fs)	Pathogenic
228407	NM_138691.3(TMC1):c.1677G>A (p.Trp559Ter)	Pathogenic
236041	NM_138691.3(TMC1):c.15dup (p.Val6fs)	Pathogenic
236042	NM_138691.3(TMC1):c.229del (p.Arg77fs)	Pathogenic
242394	NM_138691.3(TMC1):c.1810C>T (p.Arg604Ter)	Pathogenic
2427247	NC_000009.11:g.(?75231331)(75407288_?)del	Pathogenic
2443844	NM_138691.3(TMC1):c.1627G>A (p.Asp543Asn)	Pathogenic
253561	GRCh37/hg19 9q21.13(chr9:75161655-75429310)x1	Pathogenic
2683613	NM_138691.3(TMC1):c.1764G>A (p.Trp588Ter)	Pathogenic
2709451	NM_138691.3(TMC1):c.1780del (p.Ala594fs)	Pathogenic
2735275	NM_138691.3(TMC1):c.64+2T>C	Pathogenic
2735276	NM_138691.3(TMC1):c.247G>T (p.Glu83Ter)	Pathogenic
2735277	NM_138691.3(TMC1):c.589G>A (p.Gly197Arg)	Pathogenic
2735278	NM_138691.3(TMC1):c.790C>T (p.Arg264Ter)	Pathogenic
2735279	NM_138691.3(TMC1):c.800G>A (p.Gly267Glu)	Pathogenic
2742216	NM_138691.3(TMC1):c.1030-98_1177del	Pathogenic
2751041	NM_138691.3(TMC1):c.863_867delinsCATAATCAATACG (p.Ser288_Phe289delinsThrTer)	Pathogenic
2751167	NM_138691.3(TMC1):c.1332del (p.Arg445fs)	Pathogenic

SpliceAI

5849 predictions. Top by Δscore:

Variant	Effect	Δscore
9:72628060:G:T	donor_gain	1.0000
9:72688704:A:AG	acceptor_gain	1.0000
9:72688707:A:AG	acceptor_gain	1.0000
9:72688708:G:GG	acceptor_gain	1.0000
9:72688708:GTAC:G	acceptor_gain	1.0000
9:72688708:GTACA:G	acceptor_gain	1.0000
9:72688757:G:GG	donor_gain	1.0000
9:72694670:G:GT	donor_gain	1.0000
9:72694710:GGAGC:G	donor_gain	1.0000
9:72694711:GAGC:G	donor_gain	1.0000
9:72694711:GAGCG:G	donor_gain	1.0000
9:72694713:GC:G	donor_gain	1.0000
9:72694715:G:GG	donor_gain	1.0000
9:72700517:GA:G	acceptor_gain	1.0000
9:72700637:TTCTC:T	donor_gain	1.0000
9:72700644:G:GG	donor_gain	1.0000
9:72700661:A:AG	donor_gain	1.0000
9:72700661:A:G	donor_gain	1.0000
9:72742526:G:GG	donor_gain	1.0000
9:72754784:A:AG	acceptor_gain	1.0000
9:72754785:G:GG	acceptor_gain	1.0000
9:72754885:G:GG	donor_gain	1.0000
9:72789113:AT:A	acceptor_gain	1.0000
9:72789113:ATG:A	acceptor_gain	1.0000
9:72789114:T:TA	acceptor_gain	1.0000
9:72789226:G:GT	donor_gain	1.0000
9:72789267:G:GT	donor_gain	1.0000
9:72789268:A:T	donor_gain	1.0000
9:72789279:C:T	donor_gain	1.0000
9:72789315:G:GT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008717 (9:72814507 T>C), RS1000012274 (9:72541783 C>T), RS1000014019 (9:72805897 A>C,T), RS1000024616 (9:72821593 C>G,T), RS1000028404 (9:72726717 T>C), RS1000028431 (9:72684395 G>A), RS1000032673 (9:72593732 G>A), RS1000037349 (9:72577808 G>C), RS1000052393 (9:72588196 G>A), RS1000074540 (9:72762433 C>T), RS1000074859 (9:72821115 T>C), RS1000128019 (9:72762045 A>G), RS1000129462 (9:72581849 T>G), RS1000133906 (9:72733655 A>G), RS1000154941 (9:72729295 T>C)

Disease associations

OMIM: gene MIM:606706 | disease phenotypes: MIM:600974, MIM:606705, MIM:220290, MIM:607197, MIM:128600

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal dominant
autosomal recessive nonsyndromic hearing loss 7	Definitive	Autosomal recessive
autosomal dominant nonsyndromic hearing loss 36	Strong	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD
autosomal recessive nonsyndromic hearing loss 7	Definitive	AR

Mondo (8): autosomal recessive nonsyndromic hearing loss 7 (MONDO:0010967), hearing loss disorder (MONDO:0005365), autosomal dominant nonsyndromic hearing loss 36 (MONDO:0011708), nonsyndromic genetic hearing loss (MONDO:0019497), sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive (MONDO:0019588), ear malformation (MONDO:0007500), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (4): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare non-syndromic genetic deafness (Orphanet:87884), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0001751	Abnormal vestibular function
HP:0003577	Congenital onset
HP:0003621	Juvenile onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008360_3	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06
GCST010002_321	Refractive error	6.000000e-36

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564675	Deafness, Autosomal Dominant 36 (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C563417	Deafness, Autosomal Recessive 7 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, affects methylation	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
propionaldehyde	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases methylation	1
Fulvestrant	affects cotreatment, affects methylation, increases methylation	1
Methapyrilene	decreases methylation	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

4 cell lines: 2 induced pluripotent stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A9XF	CPGHi001-A	Induced pluripotent stem cell	Male
CVCL_B7DM	CPGHi001-A-1	Induced pluripotent stem cell	Male
CVCL_TS69	HAP1 TMC1 (-) 1	Cancer cell line	Male
CVCL_TS70	HAP1 TMC1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound