USH1C

Summary

USH1C (USH1 protein network component harmonin, HGNC:12597) is a protein-coding gene on chromosome 11p15.1, encoding Harmonin (Q9Y6N9). Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells.

This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10083 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Usher syndrome type 1 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,529 total — 76 pathogenic, 101 likely-pathogenic
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_153676

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12597
Approved symbol	USH1C
Name	USH1 protein network component harmonin
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	PDZ73, harmonin, NY-CO-37, NY-CO-38, PDZ-73, AIE-75, PDZD7C
Ensembl gene	ENSG00000006611
Ensembl biotype	protein_coding
OMIM	605242
Entrez	10083

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 TEC

ENST00000005226, ENST00000318024, ENST00000526181, ENST00000526313, ENST00000527020, ENST00000527551, ENST00000527720, ENST00000529563, ENST00000530700, ENST00000534556, ENST00000624811, ENST00000957656

RefSeq mRNA: 3 — MANE Select: NM_153676 NM_001297764, NM_005709, NM_153676

CCDS: CCDS31438, CCDS73265, CCDS7825

Canonical transcript exons

ENST00000005226 — 27 exons

Exon	Start	End
ENSE00000339040	17520870	17520994
ENSE00000705382	17521346	17521411
ENSE00000705383	17522784	17522926
ENSE00000705384	17523211	17523267
ENSE00000705385	17523419	17523478
ENSE00000705386	17524451	17524535
ENSE00000705388	17526347	17526441
ENSE00000705389	17526753	17526810
ENSE00000705390	17527016	17527040
ENSE00000705391	17527223	17527331
ENSE00000705392	17531154	17531292
ENSE00000705394	17531399	17531542
ENSE00001356343	17533255	17533322
ENSE00001368974	17510405	17510521
ENSE00001369056	17505830	17505949
ENSE00001373888	17509356	17509838
ENSE00001374202	17495569	17495677
ENSE00001374456	17504647	17504697
ENSE00001387708	17511902	17512054
ENSE00002179425	17493900	17494376
ENSE00002182900	17544272	17544416
ENSE00003496015	17501482	17501535
ENSE00003506647	17501051	17501150
ENSE00003564672	17496758	17496813
ENSE00003570131	17498162	17498271
ENSE00003586081	17501939	17501980
ENSE00003609390	17516241	17516290

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.43.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5260 / max 217.0966, expressed in 198 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118871	0.6570	126
118873	0.3364	108
118866	0.1386	30
118865	0.1300	37
118864	0.1233	37
118863	0.0482	23
118870	0.0474	14
118872	0.0283	14
118868	0.0126	8
118869	0.0043	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.76	gold quality
rectum	UBERON:0001052	96.72	gold quality
ileal mucosa	UBERON:0000331	96.67	gold quality
spinal cord	UBERON:0002240	95.44	gold quality
duodenum	UBERON:0002114	94.15	gold quality
cranial nerve II	UBERON:0000941	93.60	gold quality
gall bladder	UBERON:0002110	93.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.71	gold quality
adult mammalian kidney	UBERON:0000082	92.67	gold quality
jejunal mucosa	UBERON:0000399	92.52	gold quality
small intestine	UBERON:0002108	92.08	gold quality
transverse colon	UBERON:0001157	92.07	gold quality
pancreatic ductal cell	CL:0002079	90.48	gold quality
colonic mucosa	UBERON:0000317	90.00	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.08	gold quality
islet of Langerhans	UBERON:0000006	87.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.41	gold quality
substantia nigra	UBERON:0002038	87.23	gold quality
corpus callosum	UBERON:0002336	87.13	gold quality
kidney	UBERON:0002113	87.10	gold quality
intestine	UBERON:0000160	86.73	gold quality
midbrain	UBERON:0001891	86.27	gold quality
inferior olivary complex	UBERON:0002127	85.98	gold quality
nephron tubule	UBERON:0001231	85.22	gold quality
large intestine	UBERON:0000059	84.87	gold quality
colon	UBERON:0001155	84.61	gold quality
putamen	UBERON:0001874	84.19	gold quality
metanephros cortex	UBERON:0010533	83.49	gold quality
subthalamic nucleus	UBERON:0001906	83.15	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	15.29
E-ANND-3	yes	11.13
E-GEOD-83139	yes	3.90
E-HCAD-31	no	2.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting USH1C, 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-6867-5P	100.00	82.21	3464
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-124-5P	98.11	67.65	1095
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-556-5P	97.75	66.17	473
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-193A-5P	95.70	65.33	613
HSA-MIR-433-5P	94.67	64.82	99

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 26)

• USH1C 216G–>A mutation and the 9-repeat VNTR(t,t) allele are in complete linkage disequilibrium in the Acadian population (PMID:11810303)
• Mutations of USHIC can cause both Usher syndrome type IC and nonsyndromic recessive deafness DFNB18. (PMID:12107438)
• Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. (PMID:12136232)
• the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia (PMID:12485990)
• the instability of the USH1C mRNA is explained by the 216G–>A out-of-frame splice site mutation. (PMID:15578223)
• The c.216G>A mutation within the USH1C gene has been linked to a founder effect within the French Canadian population of Quebec associated with deafblindness. (PMID:17407589)
• The structures of the harmonin N-domain alone and in complex with the cadherin 23 internal peptide fragment uncovered the detailed binding mechanism of this interaction between harmonin and cadherin 23. (PMID:19297620)
• Mutations in harmonin and Sans found in USH1 patients are shown to destabilize the complex formation of the two proteins (PMID:20142502)
• Mutations in USH1C are responsible for 1.5% of Usher syndrome type I disease in patients of Spanish origin. (PMID:21203349)
• We report a novel molecular cause of sector retinitis pigmentosa associated with hearing loss representing a new phenotype associated with mutations in the USH1C gene. (PMID:21487335)
• Pathogenic mutations in MYO7A, USH1C, and USH1G have been found in four consanguineous Israeli Arab families with Usher syndrome type 1. (PMID:22219650)
• The data highlight the ability of ZFNs to induce targeted homologous recombination and mediate gene repair in USH. (PMID:22661463)
• Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia (PMID:22879593)
• This is the first report of a mutation in a known USH1 gene that causes late onset rather than congenital sensorineural hearing loss. (PMID:23251578)
• We localized proteins encoded by the top two regulated genes, TBL1X and USH1C, using immunohistochemistry to placental stem and anchoring villi associated with active contractile function. (PMID:23665419)
• harmonin and villin autoantibodies are sensitive and specific markers of IPEX, differentiate IPEX, including atypical cases, from other early childhood disorders associated with enteropathy (PMID:24250806)
• Description of the spectrum of mutations in USHIC in 374 families with autosomal recessive, non-syndromic hearing loss from India. (PMID:24416283)
• ANKS4B, and MYO7B form a stable ternary complex for anchoring microvilli tip-link cadherins (PMID:26812017)
• We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. (PMID:27440999)
• In summary, our studies provide novel insight into the functional relationship between USH1 and USH2 proteins in the cochlea and the retina as well as the disease mechanisms underlying USH1 and USH2. (PMID:28031293)
• The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a. (PMID:28439001)
• Harmonin can adopt two different structural states, ‘open’ and ‘closed’, as a result of the self-interaction between its domains. (PMID:28653419)
• Crystall structure shows the interactions between harmonin protein domains and its partner Myo7a. (PMID:28660889)
• Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condensed Molecular Assembly via Liquid-Liquid Phase Separation. (PMID:31644917)
• Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss. (PMID:33231815)
• Expression and subcellular localization of USH1C/harmonin in human retina provides insights into pathomechanisms and therapy. (PMID:35997788)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ush1c	ENSDARG00000051876
mus_musculus	Ush1c	ENSMUSG00000030838
rattus_norvegicus	Ush1c	ENSRNOG00000021149

Paralogs (2): WHRN (ENSG00000095397), PDZD7 (ENSG00000186862)

Protein

Protein identifiers

Harmonin — Q9Y6N9 (reviewed: Q9Y6N9)

Alternative names: Antigen NY-CO-38/NY-CO-37, Autoimmune enteropathy-related antigen AIE-75, Protein PDZ-73, Renal carcinoma antigen NY-REN-3, Usher syndrome type-1C protein

All UniProt accessions (4): Q9Y6N9, A0A0S2Z4U9, A0A0S2Z4V1, E9PNW1

UniProt curated annotations — full annotation on UniProt →

Function. Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal development and maintenance of cochlear hair cell bundles. As part of the intermicrovillar adhesion complex/IMAC plays a role in brush border differentiation, controlling microvilli organization and length. Probably plays a central regulatory role in the assembly of the complex, recruiting CDHR2, CDHR5 and MYO7B to the microvilli tips.

Subunit / interactions. Part of the IMAC/intermicrovillar adhesion complex/intermicrovillar tip-link complex composed of ANKS4B, MYO7B, USH1C, CDHR2 and CDHR5. Part of a complex composed of USH1C, USH1G and MYO7A. Interacts with F-actin. Interacts with USH2A. Interacts with SLC4A7. Interacts (via PDZ1 domain) with the C-terminus of USHBP1. Interacts (via N-terminus and PDZ 2 domain) with CDH23. Interacts with USH1G. Interacts with MYO7B. Interacts with CDHR2 and CDHR5; may mediate their interaction with MYO7B at the microvilli tip. Interacts (via PDZ 1 domain) with ANKS4B. Interacts (via PDZ 1 domain) with DOCK4.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Cell projection. Microvillus.

Tissue specificity. Expressed in small intestine, colon, kidney, eye and weakly in pancreas. Expressed also in vestibule of the inner ear.

Disease relevance. Usher syndrome 1C (USH1C) [MIM:276904] USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 18A (DFNB18A) [MIM:602092] 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. The PDZ 1 domain mediates interaction with ANKS4B, DOCK4, USHBP1, USH1G, SLC4A7. The N-terminal region constitutes an independently folded domain that has structural similarity with the CCM2 C-terminus, despite very low sequence similarity.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y6N9-1	1	yes
Q9Y6N9-2	2
Q9Y6N9-3	3
Q9Y6N9-4	4
Q9Y6N9-5	5

RefSeq proteins (3): NP_001284693, NP_005700, NP_710142* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR030237	Harmonin_N	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR051844	USH2_Complex_Protein	Family

Pfam: PF00595, PF21219

UniProt features (61 total): helix 20, strand 19, splice variant 5, domain 3, sequence conflict 3, region of interest 3, turn 2, chain 1, sequence variant 1, mutagenesis site 1, coiled-coil region 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
5XBF	X-RAY DIFFRACTION	1.8
7X2E	X-RAY DIFFRACTION	1.85
5MV8	X-RAY DIFFRACTION	1.88
3K1R	X-RAY DIFFRACTION	2.3
5MV9	X-RAY DIFFRACTION	2.6
5F3X	X-RAY DIFFRACTION	2.65
1X5N	SOLUTION NMR
2KBQ	SOLUTION NMR
2KBR	SOLUTION NMR
2KBS	SOLUTION NMR
2LSR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6N9-F1	79.51	0.37

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): 219

Mutagenesis-validated functional residues (1):

Position	Phenotype
103	strongly reduced affinity for ush1g.

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: 0 (showing top):

GO Biological Process (18): G2/M transition of mitotic cell cycle (GO:0000086), auditory receptor cell morphogenesis (GO:0002093), sensory perception of sound (GO:0007605), parallel actin filament bundle assembly (GO:0030046), regulation of microvillus length (GO:0032532), inner ear morphogenesis (GO:0042472), inner ear auditory receptor cell differentiation (GO:0042491), photoreceptor cell maintenance (GO:0045494), retinal cone cell development (GO:0046549), sensory perception of light stimulus (GO:0050953), equilibrioception (GO:0050957), actin filament bundle assembly (GO:0051017), inner ear receptor cell stereocilium organization (GO:0060122), protein-containing complex assembly (GO:0065003), protein localization to microvillus (GO:1904106), brush border assembly (GO:1904970), cell differentiation (GO:0030154), neuromuscular process controlling balance (GO:0050885)

GO Molecular Function (2): spectrin binding (GO:0030507), protein binding (GO:0005515)

GO Cellular Component (15): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), stereocilia ankle link complex (GO:0002142), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), microvillus (GO:0005902), brush border (GO:0005903), cilium (GO:0005929), stereocilium (GO:0032420), stereocilium tip (GO:0032426), apical part of cell (GO:0045177), synapse (GO:0045202), cell projection (GO:0042995)

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	7
cellular component assembly	3
embryonic morphogenesis	2
sensory perception	2
actin-based cell projection	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
inner ear morphogenesis	1
cell morphogenesis involved in neuron differentiation	1
auditory receptor cell development	1
sensory perception of mechanical stimulus	1
actin filament bundle assembly	1
regulation of microvillus organization	1
regulation of cell projection size	1
ear morphogenesis	1
inner ear development	1
hair cell differentiation	1
inner ear receptor cell differentiation	1
retina homeostasis	1
multicellular organismal process	1
eye photoreceptor cell development	1
retinal cone cell differentiation	1
neuromuscular process controlling balance	1
actin filament bundle organization	1
neuron projection development	1
inner ear receptor cell development	1
protein-containing complex organization	1
protein localization to actin cytoskeleton	1
cellular developmental process	1
musculoskeletal movement	1
neuromuscular process	1
cytoskeletal protein binding	1
protein-containing complex binding	1
binding	1
photoreceptor cell cilium	1
stereocilia ankle link	1
protein-containing complex	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

242 interactions, top by confidence:

A	B	Type	Score
USH1G	USH1C	psi-mi:“MI:0915”(physical association)	0.960
USH1C	USH1G	psi-mi:“MI:0407”(direct interaction)	0.960
USH1G	USH1C	psi-mi:“MI:2364”(proximity)	0.960
USH1C	USH1G	psi-mi:“MI:0915”(physical association)	0.960
USH1C	RAC1	psi-mi:“MI:0915”(physical association)	0.560
MIPOL1	USH1C	psi-mi:“MI:0915”(physical association)	0.560
USH1C	CTNNAL1	psi-mi:“MI:0915”(physical association)	0.560
USH1C	MIPOL1	psi-mi:“MI:0915”(physical association)	0.560
CTNNAL1	USH1C	psi-mi:“MI:0915”(physical association)	0.560
USH1C		psi-mi:“MI:0407”(direct interaction)	0.560
USH1C	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.550
USH1G	POTEF	psi-mi:“MI:0914”(association)	0.530
USH1C	CDH23	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (49): USH1C (Two-hybrid), USH1C (Two-hybrid), MIPOL1 (Two-hybrid), USH1C (Affinity Capture-MS), TUBA3C (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), LTV1 (Affinity Capture-MS), USH1C (Affinity Capture-MS), USH1C (Affinity Capture-MS), USH1C (Affinity Capture-MS), USH1G (Affinity Capture-MS), USH1C (Affinity Capture-MS), WDR20 (Affinity Capture-MS), SLC9A3R2 (Affinity Capture-MS), USH1C (Two-hybrid)

ESM2 similar proteins: A2VEA3, A5PKA5, A7MB76, O70133, O89050, P09851, P17427, P18484, P20595, P20936, P49336, P50904, P79101, P97834, Q08211, Q12800, Q28141, Q2MHE5, Q2TBL9, Q32NS4, Q3MHJ2, Q3UHD6, Q5M887, Q5R4Q7, Q5R874, Q5RB35, Q5RBN9, Q5RCG0, Q6GR10, Q6P5H6, Q6PKX4, Q7SXR3, Q7T2U9, Q7Z6J6, Q86TJ2, Q8K4V4, Q8N653, Q8R3L8, Q8R3S6, Q96DM3

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, A5PKA5, F1MCA7, G5ECY0, O14907, O14910, O35274, O35867, O55164, O61967, O62674, O62675, O62676, O88951, O88952, P31016, P57105, P70175, P70587, P78352, P97879, Q0P5E6, Q0P5F3, Q12959, Q13424, Q13425, Q13884, Q14160, Q15599, Q22638, Q28626, Q28C55, Q2KIB6, Q32LE7, Q32LM6, Q3T0C9, Q3UHD6, Q4H4B6, Q5EBL8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
USH1C	“form complex”	“TIP-LINK complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Assembly and cell surface presentation of NMDA receptors	12	44.1×	7e-15
Ras activation upon Ca2+ influx through NMDA receptor	5	41.4×	7e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	39.4×	7e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	39.4×	7e-06
Dopamine Neurotransmitter Release Cycle	5	36.0×	1e-05
Long-term potentiation	5	34.5×	1e-05
Neurexins and neuroligins	11	31.4×	5e-12
Protein-protein interactions at synapses	7	26.9×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	60.5×	3e-13
protein localization to synapse	6	47.9×	5e-07
receptor clustering	7	45.5×	4e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	6	31.0×	3e-06
protein-containing complex assembly	10	11.9×	2e-06
cell-cell adhesion	10	10.6×	3e-06
protein localization to plasma membrane	6	6.8×	6e-03
chemical synaptic transmission	7	5.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1529 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	76
Likely pathogenic	101
Uncertain significance	461
Likely benign	657
Benign	108

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031570	NM_153676.4(USH1C):c.586C>T (p.Arg196Ter)	Pathogenic
1072243	NC_000011.9:g.(?17522578)(17523547_?)del	Pathogenic
1072244	NC_000011.9:g.(?17526184)(17548597_?)del	Pathogenic
1072317	NM_005709.4(USH1C):c.1225G>T (p.Glu409Ter)	Pathogenic
1075119	NM_153676.4(USH1C):c.1099G>T (p.Glu367Ter)	Pathogenic
1350655	NM_153676.4(USH1C):c.364C>T (p.Gln122Ter)	Pathogenic
1357932	NM_153676.4(USH1C):c.238_239insT (p.Arg80fs)	Pathogenic
1392718	NM_153676.4(USH1C):c.1050del (p.Glu351fs)	Pathogenic
1422631	NM_153676.4(USH1C):c.348_373del (p.His116fs)	Pathogenic
1441997	NM_005709.4(USH1C):c.1241_1242dup (p.Ala415fs)	Pathogenic
1451480	NM_153676.4(USH1C):c.579+2T>G	Pathogenic
1458123	NM_153676.4(USH1C):c.2227-2A>G	Pathogenic
1458556	NC_000011.9:g.(?17548750)(17565854_?)del	Pathogenic
1459455	NC_000011.9:g.(?17552691)(17565973_?)del	Pathogenic
1460152	NC_000011.9:g.(?17552681)(17552859_?)del	Pathogenic
1939547	NM_153676.4(USH1C):c.496_496+4del	Pathogenic
1945035	NM_153676.4(USH1C):c.183dup (p.Ile62fs)	Pathogenic
2011674	NM_153676.4(USH1C):c.1068C>G (p.Tyr356Ter)	Pathogenic
2050742	NM_005709.4(USH1C):c.1282C>T (p.Gln428Ter)	Pathogenic
2114020	NM_153676.4(USH1C):c.1188del (p.Val397fs)	Pathogenic
2116425	NM_153676.4(USH1C):c.2281G>T (p.Glu761Ter)	Pathogenic
2126907	NM_153676.4(USH1C):c.901del (p.Arg301fs)	Pathogenic
2135834	NM_153676.4(USH1C):c.695del (p.Gln232fs)	Pathogenic
218193	NM_153676.4(USH1C):c.7C>T (p.Arg3Ter)	Pathogenic
2425405	NC_000011.9:g.(?17522588)(17527506_?)del	Pathogenic
2503072	NM_153676.4(USH1C):c.777del (p.Glu260fs)	Pathogenic
2703540	NM_153676.4(USH1C):c.658del (p.Arg220fs)	Pathogenic
2711187	NM_153676.4(USH1C):c.547C>T (p.Gln183Ter)	Pathogenic
2721668	NM_153676.4(USH1C):c.496+2T>A	Pathogenic
2735558	NM_153676.4(USH1C):c.590del (p.Gly197fs)	Pathogenic

SpliceAI

4611 predictions. Top by Δscore:

Variant	Effect	Δscore
11:17512071:T:TC	acceptor_gain	1.0000
11:17520868:A:AC	donor_gain	1.0000
11:17520869:C:CC	donor_gain	1.0000
11:17520869:CA:C	donor_gain	1.0000
11:17521337:GGTAC:G	donor_loss	1.0000
11:17521338:GTACT:G	donor_loss	1.0000
11:17521339:TACT:T	donor_loss	1.0000
11:17521340:ACTC:A	donor_loss	1.0000
11:17521341:C:CG	donor_loss	1.0000
11:17521342:TCA:T	donor_loss	1.0000
11:17521343:CA:C	donor_loss	1.0000
11:17521344:A:AC	donor_gain	1.0000
11:17521344:AC:A	donor_loss	1.0000
11:17521345:C:CT	donor_gain	1.0000
11:17521345:CT:C	donor_gain	1.0000
11:17521345:CTGTT:C	donor_gain	1.0000
11:17521407:TCCTT:T	acceptor_gain	1.0000
11:17521408:CCTTC:C	acceptor_gain	1.0000
11:17521409:CTT:C	acceptor_gain	1.0000
11:17521410:TT:T	acceptor_gain	1.0000
11:17521412:C:CC	acceptor_gain	1.0000
11:17522779:CTCA:C	donor_gain	1.0000
11:17522780:TCA:T	donor_loss	1.0000
11:17522781:CA:C	donor_loss	1.0000
11:17522782:A:AC	donor_gain	1.0000
11:17522782:ACTG:A	donor_gain	1.0000
11:17522782:ACTGC:A	donor_gain	1.0000
11:17522783:C:A	donor_loss	1.0000
11:17522783:C:CT	donor_gain	1.0000
11:17522783:CTG:C	donor_gain	1.0000

AlphaMissense

5864 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:17531510:A:G	L46P	1.000
11:17526788:A:G	W182R	0.999
11:17526788:A:T	W182R	0.999
11:17527261:A:G	L153P	0.999
11:17527312:C:G	R136P	0.999
11:17527327:C:T	G131E	0.999
11:17531426:T:G	Y74S	0.999
11:17531427:A:C	Y74D	0.999
11:17531427:A:G	Y74H	0.999
11:17533270:A:G	L30P	0.999
11:17523254:A:G	L278P	0.998
11:17523465:A:C	I258S	0.998
11:17523465:A:T	I258N	0.998
11:17524533:A:T	I226N	0.998
11:17527025:G:T	P171H	0.998
11:17527318:A:T	I134N	0.998
11:17527327:C:A	G131V	0.998
11:17527328:C:A	G131W	0.998
11:17527328:C:G	G131R	0.998
11:17527328:C:T	G131R	0.998
11:17531158:A:G	L128P	0.998
11:17531272:A:G	L90P	0.998
11:17531427:A:T	Y74N	0.998
11:17531450:A:T	I66N	0.998
11:17531453:A:G	L65P	0.998
11:17531522:A:G	L42P	0.998
11:17533262:A:C	Y33D	0.998
11:17533282:A:G	L26P	0.998
11:17544281:G:C	F9L	0.998
11:17544281:G:T	F9L	0.998

dbSNP variants (sampled 300 via entrez): RS1000128507 (11:17527610 G>A), RS1000142490 (11:17516792 G>A,T), RS1000184536 (11:17532968 T>A,C), RS1000211079 (11:17509991 C>T), RS1000418567 (11:17522336 C>T), RS1000430837 (11:17504220 G>A,C), RS1000526859 (11:17538361 G>A), RS1000527785 (11:17499436 A>C,G), RS1000638885 (11:17544753 T>TTA,TTC), RS1000726854 (11:17499121 G>A), RS1000768385 (11:17493532 G>A), RS1000780029 (11:17531489 G>C,T), RS1000828049 (11:17543851 C>G), RS1000846422 (11:17526200 C>T), RS1000891758 (11:17516858 G>A)

Disease associations

OMIM: gene MIM:605242 | disease phenotypes: MIM:276904, MIM:602092, MIM:276900, MIM:220290, MIM:607197, MIM:268000, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
Usher syndrome type 1C	Definitive	Autosomal recessive
Usher syndrome type 1	Definitive	Unknown
autosomal recessive nonsyndromic hearing loss 18A	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
nonsyndromic genetic hearing loss	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AR
Usher syndrome type 1	Definitive	AR

Mondo (12): Usher syndrome type 1C (MONDO:0010171), autosomal recessive nonsyndromic hearing loss 18A (MONDO:0011192), hearing loss disorder (MONDO:0005365), Usher syndrome (MONDO:0019501), Usher syndrome type 1 (MONDO:0010168), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), hearing loss, autosomal recessive (MONDO:0019588), Usher syndrome type 2 (MONDO:0016484), retinitis pigmentosa (MONDO:0019200), Meniere disease (MONDO:0007972), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (9): Usher syndrome type 1 (Orphanet:231169), Usher syndrome (Orphanet:886), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Usher syndrome type 2 (Orphanet:231178), Retinitis pigmentosa (Orphanet:791), Rare genetic deafness (Orphanet:96210), NON RARE IN EUROPE: Menière disease (Orphanet:45360)

HPO phenotypes

23 total (24 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000375	Abnormal cochlea morphology
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000550	Undetectable electroretinogram
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001270	Motor delay
HP:0001751	Abnormal vestibular function
HP:0001756	Vestibular hyporeflexia
HP:0002141	Gait imbalance
HP:0003593	Infantile onset
HP:0007663	Reduced visual acuity
HP:0007994	Peripheral visual field loss
HP:0008527	Congenital sensorineural hearing impairment
HP:0008555	Absent vestibular function
HP:0000556	Retinal dystrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003542_112	Night sleep phenotypes	2.000000e-06
GCST005951_67	Body mass index	6.000000e-09
GCST005951_68	Body mass index	3.000000e-09
GCST006976_115	Macular thickness	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008575	Meniere Disease	C09.218.568.217.500
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C564609	Deafness, Autosomal Recessive (supp.)
C566580	Deafness, Autosomal Recessive 18 (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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation	2
Valproic Acid	affects expression, increases expression	2
dicrotophos	increases expression	1
bisphenol A	decreases methylation	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
S 1 (combination)	increases response to substance	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	affects response to substance	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zinc	decreases expression	1
Aflatoxin B1	affects methylation	1

Cellosaurus cell lines

20 cell lines: 19 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AU40	GM09067	Transformed cell line	Female
CVCL_AU42	GM09069	Transformed cell line	Male
CVCL_AU43	GM09070	Transformed cell line	Male
CVCL_AU44	GM09071	Transformed cell line	Female
CVCL_AU45	GM09072	Transformed cell line	Male
CVCL_AU46	GM09073	Transformed cell line	Female
CVCL_AU47	GM09074	Transformed cell line	Female
CVCL_AU49	GM09076	Transformed cell line	Male
CVCL_AU50	GM09077	Transformed cell line	Male
CVCL_AU63	GM09456	Transformed cell line	Female

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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
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