PDZD7

Summary

PDZD7 (PDZ domain containing 7, HGNC:26257) is a protein-coding gene on chromosome 10q24.31, encoding PDZ domain-containing protein 7 (Q9H5P4). In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links.

This gene encodes a ciliary protein homologous to proteins which are mutated in Usher syndrome patients, and mutations and translocations involving this gene have been associated with two types of Usher syndrome. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 79955 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,130 total — 71 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_001195263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26257
Approved symbol	PDZD7
Name	PDZ domain containing 7
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23209, bA108L7.8
Ensembl gene	ENSG00000186862
Ensembl biotype	protein_coding
OMIM	612971
Entrez	79955

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000370215, ENST00000470414, ENST00000474125, ENST00000619208, ENST00000642474, ENST00000644576, ENST00000644782, ENST00000645349, ENST00000646029, ENST00000912190

RefSeq mRNA: 3 — MANE Select: NM_001195263 NM_001195263, NM_001351044, NM_024895

CCDS: CCDS31269, CCDS73182

Canonical transcript exons

ENST00000619208 — 17 exons

Exon	Start	End
ENSE00001452094	101015636	101015811
ENSE00001452095	101016377	101016427
ENSE00001618361	101022209	101022385
ENSE00001779253	101023436	101023610
ENSE00001785651	101021798	101021945
ENSE00003476685	101020618	101020678
ENSE00003539385	101023928	101024068
ENSE00003574479	101018099	101018296
ENSE00003602176	101029994	101030384
ENSE00003633505	101018822	101019217
ENSE00003689321	101012167	101012258
ENSE00003711500	101010272	101010883
ENSE00003738189	101011925	101012016
ENSE00003745373	101011690	101011761
ENSE00003748477	101009250	101009350
ENSE00003818006	101031073	101031129
ENSE00003847640	101007679	101008850

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 88.58.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5974 / max 108.5483, expressed in 880 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111076	2.1984	729
111079	0.1582	70
111077	0.1355	44
205969	0.1007	47
111078	0.0046	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	88.58	gold quality
cerebellar hemisphere	UBERON:0002245	88.04	gold quality
cerebellar cortex	UBERON:0002129	87.93	gold quality
cerebellum	UBERON:0002037	85.23	gold quality
right frontal lobe	UBERON:0002810	83.86	gold quality
prefrontal cortex	UBERON:0000451	82.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.29	gold quality
anterior cingulate cortex	UBERON:0009835	81.18	gold quality
cingulate cortex	UBERON:0003027	81.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.01	gold quality
sperm	CL:0000019	80.96	gold quality
male germ cell	CL:0000015	80.38	gold quality
frontal cortex	UBERON:0001870	78.62	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.61	gold quality
spinal cord	UBERON:0002240	78.58	gold quality
caudate nucleus	UBERON:0001873	78.57	gold quality
nucleus accumbens	UBERON:0001882	78.49	gold quality
triceps brachii	UBERON:0001509	78.36	gold quality
neocortex	UBERON:0001950	78.26	gold quality
gluteal muscle	UBERON:0002000	78.17	silver quality
cortical plate	UBERON:0005343	78.00	gold quality
tongue squamous epithelium	UBERON:0006919	78.00	gold quality
putamen	UBERON:0001874	77.68	gold quality
quadriceps femoris	UBERON:0001377	77.11	gold quality
vastus lateralis	UBERON:0001379	77.04	gold quality
pituitary gland	UBERON:0000007	76.29	gold quality
hypothalamus	UBERON:0001898	76.26	gold quality
substantia nigra	UBERON:0002038	75.72	gold quality
brain	UBERON:0000955	75.58	gold quality
adenohypophysis	UBERON:0002196	75.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-111727	yes	614.17
E-ANND-3	yes	3.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting PDZD7, 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-1303	99.65	69.77	1662
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-6807-5P	97.51	64.25	1046
HSA-MIR-8079	96.33	66.11	484
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-4259	95.68	65.25	582

Literature-anchored findings (GeneRIF, showing 12)

• PDZD7 is a new autosomal-recessive deafness-causing gene and a prime candidate gene for Usher syndrome. (PMID:19028668)
• PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. (PMID:20440071)
• PDZD7 is a scaffolding component of the ankle-link complex in stereocilia and is associated with the Usher syndrome protein network. (PMID:23055499)
• overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 beta-subunit (PMID:24962568)
• Both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. (PMID:25406310)
• Mutations in PDZD7 cause autosomal recessive non-syndromic hearing loss. (PMID:26416264)
• PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. (PMID:26849169)
• This is the first report to identify PDZD7 as an ARNSHL-associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients. (PMID:29048736)
• Three mutations in PDZD7 gene linked to autosomal recessive non-syndromic hearing loss (ARNSHL) were identified in a Chinese pedigree. The findings expand not only our knowledge of genetic causes of ARNSHL, but also PDZD7 genes mutation spectrum of the disease. They will aid personalized genetic counseling, molecular diagnostics and clinical management of this condition. (PMID:31129248)
• PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot. (PMID:31454969)
• Novel homozygous variant in the PDZD7 gene in a family with nonsyndromic sensorineural hearing loss. (PMID:35715776)
• Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia. (PMID:38956522)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pdzd7	ENSMUSG00000074818
rattus_norvegicus	Pdzd7	ENSRNOG00000032946

Paralogs (2): USH1C (ENSG00000006611), WHRN (ENSG00000095397)

Protein

Protein identifiers

PDZ domain-containing protein 7 — Q9H5P4 (reviewed: Q9H5P4)

All UniProt accessions (7): A0A2R8Y4R0, A0A2R8Y6B4, A0A2R8Y6W6, A0A2R8Y892, A0A2R8YFN1, Q9H5P4, S4R3J9

UniProt curated annotations — full annotation on UniProt →

Function. In cochlear developing hair cells, essential in organizing the USH2 complex at stereocilia ankle links. Blocks inhibition of adenylate cyclase activity mediated by ADGRV1.

Subunit / interactions. Homodimerizes (via PDZ2 domain). Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts (via PDZ domains) with WHRN; the interaction is direct. Interacts with USH1G. Interacts with ADGRV1 (via the cytoplasmic region). Interacts with USH2A (via the cytoplasmic region). Interacts with MYO7A (via MyTH4-FERM domains).

Subcellular location. Cell projection. Cilium. Nucleus. Stereocilium.

Tissue specificity. Weakly expressed in the inner ear. Expressed in the retinal pigment epithelium.

Disease relevance. Deafness, autosomal recessive, 57 (DFNB57) [MIM:618003] A form of non-syndromic, sensorineural deafness characterized by symmetric, bilateral hearing loss with onset in early childhood. Vestibular function is preserved. 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. DFNB57 severity ranges from moderate to severe. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration disrupting PDZD7 has been found in patients with non-syndromic sensorineural deafness. Translocation t(10;11),t(10;11). Usher syndrome 2C (USH2C) [MIM:605472] 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). USH2 is characterized by congenital mild hearing impairment with normal vestibular responses. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. A PDZD7 mutation has been found in combination with a mutation in ADGRV1 in a patient affected by Usher syndrome, suggesting PDZD7 mutations contribute to digenic Usher syndrome. Usher syndrome 2A (USH2A) [MIM:276901] 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). USH2 is characterized by congenital mild hearing impairment with normal vestibular responses. The gene represented in this entry acts as a disease modifier.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H5P4-3	1	yes
Q9H5P4-1	2
Q9H5P4-2	3

RefSeq proteins (3): NP_001182192, NP_001337973, NP_079171 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR042786	PDZD7_HN-like	Domain
IPR051844	USH2_Complex_Protein	Family

Pfam: PF00595

UniProt features (39 total): strand 12, sequence variant 7, compositionally biased region 4, helix 4, region of interest 4, domain 3, splice variant 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7PC5	X-RAY DIFFRACTION	1.7
2EEH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H5P4-F1	57.10	0.14

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_NEUROGENESIS, PAX2_01, PAX8_B, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GATA1_01, GOBP_EAR_MORPHOGENESIS, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS

GO Biological Process (7): sensory perception of sound (GO:0007605), establishment of protein localization (GO:0045184), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), establishment of localization in cell (GO:0051649), auditory receptor cell stereocilium organization (GO:0060088), inner ear receptor cell differentiation (GO:0060113), auditory receptor cell development (GO:0060117)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (14): stereocilia ankle link (GO:0002141), stereocilia ankle link complex (GO:0002142), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), cilium (GO:0005929), stereocilium (GO:0032420), stereocilium tip (GO:0032426), ciliary basal body (GO:0036064), USH2 complex (GO:1990696), cell projection (GO:0042995), organelle (GO:0043226), plasma membrane bounded cell projection (GO:0120025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
establishment of localization	2
protein-containing complex	2
sensory perception of mechanical stimulus	1
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
cellular localization	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
mechanoreceptor differentiation	1
inner ear development	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell development	1
protein binding	1
binding	1
stereocilia coupling link	1
stereocilia ankle link	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
stereocilium	1
microtubule organizing center	1
cilium	1
cell projection	1
plasma membrane region	1

Protein interactions and networks

STRING

844 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDZD7	ADGRV1	Q8WXG9	987
PDZD7	USH2A	O75445	976
PDZD7	USH1G	Q495M9	966
PDZD7	MYO7A	P78427	833
PDZD7	E9PNW1	E9PNW1	820
PDZD7	WHRN	Q9P202	817
PDZD7	CLRN1	P58418	802
PDZD7	CIB2	O75838	768
PDZD7	PCDH15	Q96QU1	727
PDZD7	CDH23	Q9H251	725
PDZD7	VEZT	Q9HBM0	623
PDZD7	STRC	Q7RTU9	611
PDZD7	MYO15A	Q9UKN7	607
PDZD7	CEP250	Q9BV73	604
PDZD7	SLC26A4	O43511	591

IntAct

453 interactions, top by confidence:

A	B	Type	Score
Tax	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.650
PDZD7	Tax	psi-mi:“MI:0915”(physical association)	0.650
PDZD7	E6	psi-mi:“MI:0407”(direct interaction)	0.610
PDZD7	PTEN	psi-mi:“MI:0407”(direct interaction)	0.610
PDZD7	RPS6KA1	psi-mi:“MI:0407”(direct interaction)	0.610
E6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.610
PDZD7	E6	psi-mi:“MI:0915”(physical association)	0.610
PDZD7	PTEN	psi-mi:“MI:0915”(physical association)	0.610
PDZD7	NET1	psi-mi:“MI:0407”(direct interaction)	0.610
PDZD7	ADGRV1	psi-mi:“MI:0915”(physical association)	0.510
E6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	E6	psi-mi:“MI:0407”(direct interaction)	0.440
EXOC4	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
MAP4	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGAP6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
CACNA1D	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (20): PDZD7 (Protein-peptide), PDZD7 (Affinity Capture-MS), PDZD7 (Two-hybrid), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS), PDZD7 (Synthetic Lethality), PDZD7 (Protein-peptide), PDZD7 (Affinity Capture-RNA), PDZD7 (Protein-peptide), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS), PDZD7 (Proximity Label-MS)

ESM2 similar proteins: A0JNI1, E9Q0S6, O94983, O95402, P80192, Q08AE8, Q1JQA8, Q1LZH7, Q28DG6, Q3B7I8, Q3KPL3, Q3U1V8, Q4VAC9, Q53LP3, Q5BJT1, Q5DU25, Q5HZA4, Q5JU85, Q5M836, Q5PQ30, Q5RBI7, Q5REP3, Q5XG99, Q5ZKK0, Q69YU3, Q6DCC7, Q6DEF4, Q6IPM2, Q6IQA2, Q6P606, Q76G19, Q7TSI1, Q7Z3D4, Q80Y50, Q86UU1, Q8BL43, Q8BY98, Q8C0J6, Q8CC84, Q8IV50

Diamond homologs: A1Z9P3, A1ZA47, A2ALU4, A8E0R9, D4A702, E9Q9W7, O00151, O14910, O70209, O70400, O75112, O88952, P36202, P50479, P52944, P70271, P97879, Q01613, Q09JY9, Q0P5E6, Q0P5F3, Q13424, Q13796, Q27IV2, Q28626, Q2M3G4, Q32LM6, Q3SYZ8, Q3T005, Q3T0C8, Q53GG5, Q5E9E1, Q5F425, Q5RAA5, Q5RBI7, Q5SX79, Q61234, Q62920, Q66HS7, Q6AYD6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PDZD7	“form complex”	“USH2 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 176 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
Class B/2 (Secretin family receptors)	6	9.9×	6e-03
Cardiac conduction	7	6.6×	8e-03
G alpha (q) signalling events	10	5.0×	6e-03
Signaling by GPCR	12	4.2×	6e-03
GPCR downstream signalling	11	4.2×	7e-03
Transport of small molecules	15	3.3×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of synaptic transmission, glutamatergic	5	19.4×	2e-03
establishment of protein localization	5	13.4×	6e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	10	8.2×	2e-04
transport across blood-brain barrier	7	7.8×	6e-03
G protein-coupled receptor signaling pathway	19	4.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1130 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	22
Uncertain significance	548
Likely benign	363
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072885	NM_001195263.2(PDZD7):c.1147dup (p.Trp383fs)	Pathogenic
1367613	NM_001195263.2(PDZD7):c.2220del (p.Val741fs)	Pathogenic
1396883	NM_001195263.2(PDZD7):c.2148del (p.Leu717fs)	Pathogenic
1438233	NM_001195263.2(PDZD7):c.432del (p.Thr145fs)	Pathogenic
1439598	NM_001195263.2(PDZD7):c.2440A>T (p.Lys814Ter)	Pathogenic
1451155	NM_001195263.2(PDZD7):c.2272C>T (p.Arg758Ter)	Pathogenic
1451605	NM_001195263.2(PDZD7):c.2182del (p.Leu728fs)	Pathogenic
1452742	NM_001195263.2(PDZD7):c.2462del (p.Pro821fs)	Pathogenic
1452774	NM_001195263.2(PDZD7):c.1100del (p.Asp367fs)	Pathogenic
1453154	NM_001195263.2(PDZD7):c.2568dup (p.Ser857fs)	Pathogenic
1454061	NM_001195263.2(PDZD7):c.1222del (p.Asp409fs)	Pathogenic
1455175	NM_001195263.2(PDZD7):c.918dup (p.Leu307fs)	Pathogenic
1458880	NM_001195263.2(PDZD7):c.1529dup (p.Val511fs)	Pathogenic
1806296	NM_001195263.2(PDZD7):c.668del (p.Gly223fs)	Pathogenic
1904916	NM_001195263.2(PDZD7):c.307G>A (p.Gly103Arg)	Pathogenic
1933281	NM_001195263.2(PDZD7):c.582C>A (p.Cys194Ter)	Pathogenic
1944183	NM_001195263.2(PDZD7):c.2152C>T (p.Gln718Ter)	Pathogenic
1968479	NM_001195263.2(PDZD7):c.117_121del (p.Thr40fs)	Pathogenic
1992821	NM_001195263.2(PDZD7):c.930_949dup (p.Gln317fs)	Pathogenic
1997409	NM_001195263.2(PDZD7):c.2751_2752del (p.Asn918fs)	Pathogenic
2001802	NM_001195263.2(PDZD7):c.82del (p.Arg28fs)	Pathogenic
2004023	NM_001195263.2(PDZD7):c.1185del (p.Ala396fs)	Pathogenic
2020756	NM_001195263.2(PDZD7):c.2713del (p.Leu905fs)	Pathogenic
2034019	NM_001195263.2(PDZD7):c.2082del (p.Leu695fs)	Pathogenic
2049992	NM_001195263.2(PDZD7):c.250_251insC (p.Ile84fs)	Pathogenic
2088589	NM_001195263.2(PDZD7):c.1684C>T (p.Gln562Ter)	Pathogenic
2092759	NM_001195263.2(PDZD7):c.175C>T (p.Arg59Ter)	Pathogenic
2096025	NM_001195263.2(PDZD7):c.2133del (p.His711fs)	Pathogenic
2112461	NM_001195263.2(PDZD7):c.2415del (p.Ser806fs)	Pathogenic
2423955	NC_000010.10:g.(?102783173)(102783845_?)del	Pathogenic

SpliceAI

1669 predictions. Top by Δscore:

Variant	Effect	Δscore
10:101019218:C:CC	acceptor_gain	1.0000
10:101020616:A:AC	donor_gain	1.0000
10:101020617:C:CC	donor_gain	1.0000
10:101020617:CGT:C	donor_gain	1.0000
10:101020690:A:C	acceptor_gain	1.0000
10:101020699:A:C	acceptor_gain	1.0000
10:101021793:CCCA:C	donor_loss	1.0000
10:101021794:CCA:C	donor_loss	1.0000
10:101021795:CACC:C	donor_loss	1.0000
10:101021797:C:CG	donor_loss	1.0000
10:101021941:CCACT:C	acceptor_gain	1.0000
10:101021942:CACTC:C	acceptor_gain	1.0000
10:101021944:CT:C	acceptor_gain	1.0000
10:101021946:C:CC	acceptor_gain	1.0000
10:101022191:T:TA	donor_gain	1.0000
10:101022192:C:A	donor_gain	1.0000
10:101022200:AGC:A	donor_gain	1.0000
10:101022207:A:AC	donor_gain	1.0000
10:101022208:C:CC	donor_gain	1.0000
10:101022210:TGG:T	donor_gain	1.0000
10:101022210:TGGAC:T	donor_gain	1.0000
10:101022219:AGATG:A	donor_gain	1.0000
10:101022236:T:TA	donor_gain	1.0000
10:101022237:C:CA	donor_gain	1.0000
10:101022381:CCACC:C	acceptor_gain	1.0000
10:101022382:CACC:C	acceptor_gain	1.0000
10:101022382:CACCC:C	acceptor_gain	1.0000
10:101022384:CC:C	acceptor_gain	1.0000
10:101022385:CC:C	acceptor_gain	1.0000
10:101022386:C:CC	acceptor_gain	1.0000

AlphaMissense

6636 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:101021808:A:G	L286P	1.000
10:101023957:A:T	V113D	1.000
10:101021832:A:G	L278P	0.999
10:101021883:G:T	A261D	0.999
10:101021892:A:T	V258D	0.999
10:101022245:C:T	G228E	0.999
10:101022246:C:A	G228W	0.999
10:101023999:A:G	F99S	0.999
10:101009272:G:T	A899D	0.998
10:101009286:G:C	F894L	0.998
10:101009286:G:T	F894L	0.998
10:101009288:A:G	F894L	0.998
10:101009341:A:T	I876N	0.998
10:101009343:G:C	S875R	0.998
10:101009343:G:T	S875R	0.998
10:101009345:T:G	S875R	0.998
10:101009347:A:G	I874T	0.998
10:101009350:C:T	G873D	0.998
10:101010272:C:G	G873R	0.998
10:101021844:G:T	A274D	0.998
10:101021845:C:G	A274P	0.998
10:101021868:A:G	F266S	0.998
10:101021879:G:C	N262K	0.998
10:101021879:G:T	N262K	0.998
10:101021884:C:G	A261P	0.998
10:101021887:C:G	A260P	0.998
10:101022215:A:T	V238E	0.998
10:101022246:C:G	G228R	0.998
10:101022246:C:T	G228R	0.998
10:101023580:A:C	I133S	0.998

dbSNP variants (sampled 300 via entrez): RS1000034197 (10:101028645 C>T), RS1000140222 (10:101028090 G>C), RS1000403817 (10:101025774 C>A,G), RS1000518788 (10:101021686 C>G), RS1000622305 (10:101027351 G>A), RS1000695754 (10:101027060 C>A), RS1000893896 (10:101008665 G>A,T), RS1000910310 (10:101008218 C>T), RS1000975791 (10:101015743 C>G,T), RS1001032711 (10:101015559 G>A), RS1001168908 (10:101031719 C>G), RS1001294078 (10:101010419 G>A,C), RS1001381870 (10:101020931 C>T), RS1001447646 (10:101026166 G>A), RS1001453282 (10:101014530 A>G)

Disease associations

OMIM: gene MIM:612971 | disease phenotypes: MIM:618003, MIM:605472, MIM:276901, MIM:220290, MIM:607197, MIM:276900, MIM:128600

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Definitive	Unknown
hearing loss, autosomal recessive 57	Strong	Autosomal recessive
Usher syndrome type 2C	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hearing loss, autosomal recessive	Definitive	AR

Mondo (9): hearing loss, autosomal recessive 57 (MONDO:0033201), Usher syndrome type 2C (MONDO:0011558), Usher syndrome type 2A (MONDO:0010169), hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive (MONDO:0019588), inherited retinal dystrophy (MONDO:0019118), Usher syndrome (MONDO:0019501), nonsyndromic genetic hearing loss (MONDO:0019497), ear malformation (MONDO:0007500)

Orphanet (7): Usher syndrome type 2 (Orphanet:231178), Usher syndrome (Orphanet:886), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

28 total (29 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000359	Abnormality of the inner ear
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000479	Abnormal retinal morphology
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001133	Constriction of peripheral visual field
HP:0001751	Abnormal vestibular function
HP:0002141	Gait imbalance
HP:0002360	Sleep disturbance
HP:0003593	Infantile onset
HP:0007663	Reduced visual acuity
HP:0007730	Iris hypopigmentation
HP:0007994	Peripheral visual field loss
HP:0008527	Congenital sensorineural hearing impairment
HP:0011463	Childhood onset
HP:0012378	Fatigue
HP:0032036	Reduced contrast sensitivity
HP:0000556	Retinal dystrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006921_7	Regular attendance at a pub or social club	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D058499	Retinal Dystrophies	C11.768.585.658
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.)
C580334	Nonsyndromic Deafness (supp.)
C536490	Usher syndrome, type 2A (supp.)
C536492	Usher syndrome, type 2C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation	2
dicrotophos	increases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
beta-lapachone	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
clothianidin	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Mercuric Chloride	decreases expression	1
Methapyrilene	increases methylation	1
Niclosamide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

300 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
NCT04820244	Not specified	UNKNOWN	Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study
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