LOXHD1

Summary

LOXHD1 (lipoxygenase homology PLAT domains 1, HGNC:26521) is a protein-coding gene on chromosome 18q21.1, encoding Lipoxygenase homology domain-containing protein 1 (Q8IVV2). Involved in hearing.

This gene encodes a highly conserved protein consisting entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains, thought to be involved in targeting proteins to the plasma membrane. Studies in mice show that this gene is expressed in the mechanosensory hair cells in the inner ear, and mutations in this gene lead to auditory defects, indicating that this gene is essential for normal hair cell function. Screening of human families segregating deafness identified a mutation in this gene which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 125336 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 3,054 total — 182 pathogenic, 199 likely-pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001384474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26521
Approved symbol	LOXHD1
Name	lipoxygenase homology PLAT domains 1
Location	18q21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32670, LH2D1
Ensembl gene	ENSG00000167210
Ensembl biotype	protein_coding
OMIM	613072
Entrez	125336

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000300591, ENST00000335730, ENST00000398686, ENST00000398705, ENST00000414184, ENST00000419859, ENST00000441551, ENST00000452425, ENST00000536111, ENST00000536736, ENST00000579038, ENST00000582408, ENST00000642948

RefSeq mRNA: 6 — MANE Select: NM_001384474 NM_001145472, NM_001145473, NM_001173129, NM_001308013, NM_001384474, NM_144612

CCDS: CCDS11929, CCDS45861, CCDS45862, CCDS54184, CCDS77182, CCDS92455

Canonical transcript exons

ENST00000642948 — 41 exons

Exon	Start	End
ENSE00001110996	46507538	46507712
ENSE00001111000	46509698	46509815
ENSE00001111001	46483587	46483745
ENSE00001111002	46505838	46506023
ENSE00001111005	46488972	46489142
ENSE00001111006	46485019	46485151
ENSE00001534322	46477273	46477952
ENSE00001616438	46618192	46618290
ENSE00001617763	46639616	46639800
ENSE00001647143	46604106	46604229
ENSE00001654428	46641956	46642036
ENSE00001717711	46601217	46601467
ENSE00001719559	46649155	46649269
ENSE00001743839	46610776	46610924
ENSE00001772680	46521097	46521282
ENSE00003468424	46524466	46524601
ENSE00003490103	46524708	46524917
ENSE00003499963	46594331	46594466
ENSE00003502680	46533162	46533324
ENSE00003504087	46538156	46538337
ENSE00003517093	46591933	46592068
ENSE00003533783	46529177	46529331
ENSE00003554387	46518129	46518256
ENSE00003559975	46541776	46541940
ENSE00003561964	46534335	46534451
ENSE00003564842	46560083	46560545
ENSE00003565706	46592498	46592584
ENSE00003569781	46542727	46542855
ENSE00003576951	46566257	46566449
ENSE00003612201	46563065	46563225
ENSE00003614585	46559448	46559602
ENSE00003621471	46572086	46572162
ENSE00003622773	46579630	46579784
ENSE00003625098	46545317	46545421
ENSE00003647727	46577707	46577867
ENSE00003669430	46593600	46593760
ENSE00003670025	46546895	46547058
ENSE00003689586	46557356	46557489
ENSE00003689729	46569442	46569638
ENSE00003690375	46522101	46522309
ENSE00003820811	46656904	46657220

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 85.21.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7416 / max 252.9338, expressed in 111 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171815	0.2411	58
171818	0.1694	17
171817	0.1213	34
171813	0.0913	17
171819	0.0523	19
171814	0.0337	8
171820	0.0229	16
171816	0.0071	2
208553	0.0026	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	85.21	gold quality
right testis	UBERON:0004534	84.74	gold quality
testis	UBERON:0000473	82.30	gold quality
sperm	CL:0000019	80.32	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.77	gold quality
bone marrow cell	CL:0002092	74.68	gold quality
monocyte	CL:0000576	73.81	gold quality
buccal mucosa cell	CL:0002336	73.37	gold quality
leukocyte	CL:0000738	73.26	gold quality
omental fat pad	UBERON:0010414	68.88	gold quality
peritoneum	UBERON:0002358	68.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.36	gold quality
blood	UBERON:0000178	66.93	gold quality
upper arm skin	UBERON:0004263	64.35	gold quality
apex of heart	UBERON:0002098	63.36	gold quality
pituitary gland	UBERON:0000007	63.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	63.30	gold quality
putamen	UBERON:0001874	62.49	gold quality
right lung	UBERON:0002167	62.09	gold quality
upper lobe of left lung	UBERON:0008952	61.43	gold quality
caudate nucleus	UBERON:0001873	61.13	gold quality
granulocyte	CL:0000094	60.71	gold quality
tendon of biceps brachii	UBERON:0008188	60.58	gold quality
upper lobe of lung	UBERON:0008948	60.41	gold quality
metanephros cortex	UBERON:0010533	58.88	gold quality
adenohypophysis	UBERON:0002196	58.64	gold quality
spleen	UBERON:0002106	58.47	gold quality
vena cava	UBERON:0004087	58.35	gold quality
heart left ventricle	UBERON:0002084	58.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting LOXHD1, 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-944	99.82	70.85	3042
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-4797-3P	97.48	67.14	989
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-3943	95.87	64.57	523

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 16)

• A mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL), was identified. (PMID:19732867)
• A founder mutation R1572X in the LOXHD1 causes autosomal recessive hearing loss in Ashkenazi Jews (PMID:21465660)
• This is the second reported mutation in the LOXHD1 gene, and its homozygous presence in two of 39 Ashkenazi Jewish families with congenital ARNSHL suggest that it could account for some 5% of the familial cases in this community (PMID:21465660)
• Authors identified a missense change in LOXHD1. Data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes. (PMID:22341973)
• Mutations in LOXHD1 are identified in a Japanese population with sensorineural hearing loss. (PMID:25792669)
• We report a Japanese family carrying compound heterozygotes of truncating and nontruncating mutations in LOXHD1 identified by targeted NGS analysis. The fact of lower degree of hearing impairment in our cases than previously reported and the molecular modeling of the missense mutant provide insight to the genotype-phenotype correlation of DFNB77. (PMID:26973026)
• Analysis of SLC4A11, ZEB1, LOXHD1, COL8A2 and TCF4 gene sequences in a multi-generational family with late-onset Fuchs corneal dystrophy found no evidence for found polymorophisms causing the disease in this specific pedigree. (PMID:27121161)
• We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of Fuchs corneal dystrophy in carriers. (PMID:29676012)
• While mutations in ZEB1 contributed to 2% of the late-onset Fuchs’ endothelial corneal dystrophy (FECD) cases, the exact role of the two variant of uncertain significance (VUS) identified in ZEB1 and LOXHD1 in FECD pathogenesis needs to be studied. (PMID:29799290)
• Results demonstrated that a novel missense variant, LOXHD1: c.5948C > T, was associated with non-progressive Deafness, autosomal recessive 77 in a Chinese family under consanguineous marriage. (PMID:30760222)
• By analyzing the largest number of patients with LOXHD1 related hearing loss yet to be reported, we determined several characteristics of LOXHD1 variations, and recurrent variants (PMID:31547530)
• The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. (PMID:31709873)
• Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families. (PMID:32149082)
• Rising of LOXHD1 as a signature causative gene of down-sloping hearing loss in people in their teens and 20s. (PMID:33753533)
• Recessive LOXHD1 variants cause a prelingual down-sloping hearing loss: genotype-phenotype correlation and three additional children with novel variants. (PMID:33892339)
• Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1. (PMID:35705030)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	loxhd1b	ENSDARG00000074638
danio_rerio	loxhd1a	ENSDARG00000094738
mus_musculus	Loxhd1	ENSMUSG00000032818
rattus_norvegicus	Loxhd1	ENSRNOG00000017410

Paralogs (10): PKD1 (ENSG00000008710), PKD2L2 (ENSG00000078795), PKD2L1 (ENSG00000107593), PKD2 (ENSG00000118762), PKDREJ (ENSG00000130943), PKD1L1 (ENSG00000158683), PKD1L2 (ENSG00000166473), DENND5B (ENSG00000170456), DENND5A (ENSG00000184014), PKD1L3 (ENSG00000277481)

Protein

Protein identifiers

Lipoxygenase homology domain-containing protein 1 — Q8IVV2 (reviewed: Q8IVV2)

All UniProt accessions (9): A0A2R8Y7K4, C9IYQ1, C9J269, C9JMG7, Q8IVV2, F5GXP0, F5GZB4, J3KRE7, J3QKX9

UniProt curated annotations — full annotation on UniProt →

Function. Involved in hearing. Required for normal function of hair cells in the inner ear.

Subcellular location. Cell projection. Stereocilium.

Disease relevance. Deafness, autosomal recessive, 77 (DFNB77) [MIM:613079] A form of non-syndromic deafness characterized by preserved low-frequency hearing, and a trend toward mild to moderate mid-frequency and high-frequency hearing loss during childhood and adolescence. Hearing loss progresses to become moderate to severe at mid and high frequencies during adulthood. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8IVV2-1	1	yes
Q8IVV2-3	3
Q8IVV2-4	4
Q8IVV2-5	5

RefSeq proteins (6): NP_001138944, NP_001138945, NP_001166600, NP_001294942, NP_001371403, NP_653213 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001024	PLAT/LH2_dom	Domain
IPR036392	PLAT/LH2_dom_sf	Homologous_superfamily
IPR052970	Inner_ear_hair_cell_LOXHD	Family

Pfam: PF01477

UniProt features (33 total): domain 15, sequence variant 7, splice variant 5, sequence conflict 5, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVV2-F1	84.00	0.29

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 39 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, AACTTT_UNKNOWN, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, DOUGLAS_BMI1_TARGETS_UP, CART1_01, TAATTA_CHX10_01, GOCC_STEREOCILIUM_BUNDLE, GOCC_CLUSTER_OF_ACTIN_BASED_CELL_PROJECTIONS, GOCC_ACTIN_BASED_CELL_PROJECTION, YTAAYNGCT_UNKNOWN, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, chr18q21, GSE14386_UNTREATED_VS_IFNA_TREATED_ACT_PBMC_MS_PATIENT_UP, MIR6885_3P

GO Biological Process (1): sensory perception of sound (GO:0007605)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): stereocilium (GO:0032420), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	1
binding	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
cellular anatomical structure	1

Protein interactions and networks

STRING

922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LOXHD1	AGBL1	Q96MI9	815
LOXHD1	SLC4A11	Q8NBS3	799
LOXHD1	PLAT	P00750	791
LOXHD1	TMC1	Q8TDI8	774
LOXHD1	MYO3A	Q8NEV4	742
LOXHD1	MYO15A	Q9UKN7	719
LOXHD1	COL8A2	P25067	712
LOXHD1	TMPRSS3	P57727	706
LOXHD1	PCDH15	Q96QU1	701
LOXHD1	OTOF	Q9HC10	695
LOXHD1	CDH23	Q9H251	682
LOXHD1	STRC	Q7RTU9	676
LOXHD1	KANK4	Q5T7N3	648
LOXHD1	SLC26A4	O43511	639
LOXHD1	OTOA	Q7RTW8	629

IntAct

3 interactions, top by confidence:

A	B	Type	Score
LOXHD1	NOLC1	psi-mi:“MI:0915”(physical association)	0.400
FKBP4	LOXHD1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): LOXHD1 (Two-hybrid), LOXHD1 (Affinity Capture-MS), LOXHD1 (Affinity Capture-MS), LOXHD1 (Proximity Label-MS), LOXHD1 (Affinity Capture-MS), LOXHD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A075F932, A0JJX5, A8KBH6, B6ETT4, C8YR32, P04409, P05126, P05130, P05696, P05771, P05772, P10102, P17252, P20444, P21579, P21707, P24505, P24506, P29101, P41823, P46096, P46097, P47191, P48018, P68403, P68404, P90980, Q15111, Q16974, Q25378, Q32NH8, Q3TZZ7, Q3USB7, Q5FWL4, Q5R4J5, Q60HC0, Q62688, Q7LZQ8, Q7SY24, Q7XA06

Diamond homologs: A2RSQ0, C8YR32, G3V7Q0, Q5FVJ0, Q6IQ26, Q6NXD8, Q6P3S1, Q6PAL8, Q6ZUT9, Q8BIJ7, Q8C4S8, Q8CFK6, Q8IV53, Q8IVV2, Q8RXA7, Q8WXG6, Q96T51, Q9TXP3, B8UU59, E7FKV8, O08852, O16025, P09917, P12527, P48999, P51399, P98161, Q09624, Q2EG98, Q7TN88, Q7Z442, Q7Z443, Q8R526, Q8TDX9, Q9NTG1, Q9Z0T6, D3ZKX9, D3ZQF9, F1LQ70, O15296

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3054 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	182
Likely pathogenic	199
Uncertain significance	869
Likely benign	1452
Benign	78

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068488	NM_001384474.1(LOXHD1):c.3094_3095insT (p.Asn1032fs)	Pathogenic
1068820	NM_001384474.1(LOXHD1):c.3570_3571insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAACACGGTGAAACCCCGTCTCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAGAATGCGGGC (p.Thr1191fs)	Pathogenic
1069065	NM_001384474.1(LOXHD1):c.4627del (p.Glu1543fs)	Pathogenic
1069261	NM_001384474.1(LOXHD1):c.2596C>T (p.Gln866Ter)	Pathogenic
1069745	NM_001384474.1(LOXHD1):c.4477G>T (p.Glu1493Ter)	Pathogenic
1070000	NM_001384474.1(LOXHD1):c.6427_6428del (p.Ser2143fs)	Pathogenic
1070825	NM_001384474.1(LOXHD1):c.3573del (p.Asp1192fs)	Pathogenic
1071207	NM_001384474.1(LOXHD1):c.5764A>T (p.Lys1922Ter)	Pathogenic
1071600	NM_001384474.1(LOXHD1):c.4887C>A (p.Tyr1629Ter)	Pathogenic
1073276	NM_001384474.1(LOXHD1):c.4480_4481dup (p.Tyr1495fs)	Pathogenic
1075237	NC_000018.9:g.(?44087491)(44089788_?)del	Pathogenic
1075298	NM_001384474.1(LOXHD1):c.2879C>A (p.Ser960Ter)	Pathogenic
1076810	NM_001384474.1(LOXHD1):c.757C>T (p.Gln253Ter)	Pathogenic
1185685	NM_001384474.1(LOXHD1):c.6541del (p.Ala2181fs)	Pathogenic
1297637	NM_001384474.1(LOXHD1):c.3748+1G>C	Pathogenic
1319170	NM_001384474.1(LOXHD1):c.3351-1G>C	Pathogenic
1323244	NM_001384474.1(LOXHD1):c.1228C>T (p.Gln410Ter)	Pathogenic
1351875	NM_001384474.1(LOXHD1):c.4529del (p.Thr1510fs)	Pathogenic
1352206	NM_001384474.1(LOXHD1):c.469dup (p.Arg157fs)	Pathogenic
1356361	NC_000018.10:g.46656909_46657366del	Pathogenic
1357057	NM_001384474.1(LOXHD1):c.4386C>G (p.Tyr1462Ter)	Pathogenic
1357257	NM_001384474.1(LOXHD1):c.1883del (p.Gly628fs)	Pathogenic
1370392	NM_001384474.1(LOXHD1):c.5437dup (p.Ile1813fs)	Pathogenic
1375387	NM_001384474.1(LOXHD1):c.6155del (p.Asn2052fs)	Pathogenic
1376099	NM_001384474.1(LOXHD1):c.6508_6515del (p.Thr2170fs)	Pathogenic
1377068	NM_001384474.1(LOXHD1):c.5767C>T (p.Gln1923Ter)	Pathogenic
1380580	NM_001384474.1(LOXHD1):c.752_756del (p.Leu251fs)	Pathogenic
1393232	NM_001384474.1(LOXHD1):c.919del (p.Val307fs)	Pathogenic
1393322	NM_001384474.1(LOXHD1):c.2289del (p.Ser764fs)	Pathogenic
1405586	NM_001384474.1(LOXHD1):c.3847G>T (p.Glu1283Ter)	Pathogenic

SpliceAI

8087 predictions. Top by Δscore:

Variant	Effect	Δscore
18:46483561:T:TA	donor_gain	1.0000
18:46483585:A:AC	donor_gain	1.0000
18:46483586:C:CC	donor_gain	1.0000
18:46483586:CA:C	donor_gain	1.0000
18:46483597:A:AC	donor_gain	1.0000
18:46483598:C:CC	donor_gain	1.0000
18:46483600:C:CA	donor_gain	1.0000
18:46485017:A:AC	donor_gain	1.0000
18:46485018:C:CC	donor_gain	1.0000
18:46485020:T:TA	donor_gain	1.0000
18:46485021:C:A	donor_gain	1.0000
18:46485077:T:TA	donor_gain	1.0000
18:46488970:A:AC	donor_gain	1.0000
18:46488971:C:CC	donor_gain	1.0000
18:46488971:CTGGT:C	donor_gain	1.0000
18:46488980:T:TA	donor_gain	1.0000
18:46489140:TCC:T	acceptor_gain	1.0000
18:46489141:CCC:C	acceptor_gain	1.0000
18:46507558:A:C	donor_gain	1.0000
18:46507594:T:TA	donor_gain	1.0000
18:46507710:GATC:G	acceptor_loss	1.0000
18:46507711:ATCT:A	acceptor_loss	1.0000
18:46507712:TCTGG:T	acceptor_loss	1.0000
18:46507713:CTG:C	acceptor_loss	1.0000
18:46507714:T:C	acceptor_loss	1.0000
18:46509696:AC:A	donor_gain	1.0000
18:46509697:CC:C	donor_gain	1.0000
18:46509697:CCCT:C	donor_gain	1.0000
18:46509813:AACC:A	acceptor_loss	1.0000
18:46509816:C:CC	acceptor_gain	1.0000

AlphaMissense

15158 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:46483633:A:G	W1893R	1.000
18:46483633:A:T	W1893R	1.000
18:46509712:A:G	W1629R	1.000
18:46509712:A:T	W1629R	1.000
18:46529250:C:T	G1280E	1.000
18:46534382:A:G	W1183R	1.000
18:46534382:A:T	W1183R	1.000
18:46534417:C:G	R1171P	1.000
18:46483626:A:T	V1895D	0.999
18:46521249:A:G	W1501R	0.999
18:46521249:A:T	W1501R	0.999
18:46524775:A:G	F1352S	0.999
18:46524830:A:G	W1334R	0.999
18:46524830:A:T	W1334R	0.999
18:46524859:C:G	R1324P	0.999
18:46529250:C:A	G1280V	0.999
18:46529251:C:G	G1280R	0.999
18:46529251:C:T	G1280R	0.999
18:46533248:A:G	L1224P	0.999
18:46533254:C:G	R1222P	0.999
18:46533289:C:A	W1210C	0.999
18:46533289:C:G	W1210C	0.999
18:46533291:A:G	W1210R	0.999
18:46533291:A:T	W1210R	0.999
18:46534357:C:G	R1191P	0.999
18:46541926:A:G	W1049R	0.999
18:46541926:A:T	W1049R	0.999
18:46557402:A:G	W896R	0.999
18:46557402:A:T	W896R	0.999
18:46477600:A:G	W2026R	0.998

dbSNP variants (sampled 300 via entrez): RS1000000212 (18:46566190 C>G,T), RS1000002657 (18:46528044 C>G), RS1000002941 (18:46563494 C>A), RS1000004454 (18:46502582 G>T), RS1000022753 (18:46536227 C>T), RS1000043133 (18:46654466 G>A,C), RS1000079604 (18:46614002 A>G), RS1000079936 (18:46552203 G>C), RS1000095186 (18:46654665 A>G), RS1000102159 (18:46572668 C>G,T), RS1000136748 (18:46585623 G>A), RS1000173693 (18:46572374 G>A), RS1000177477 (18:46534037 T>A), RS1000192813 (18:46502032 T>C), RS1000218925 (18:46517158 T>C)

Disease associations

OMIM: gene MIM:613072 | disease phenotypes: MIM:613079, MIM:108300, MIM:242840, MIM:614231, MIM:192350, MIM:124900, MIM:220290, MIM:607197, MIM:613659

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 77	Definitive	Autosomal recessive
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
Fuchs’ endothelial dystrophy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (11): autosomal recessive nonsyndromic hearing loss 77 (MONDO:0013119), hearing loss disorder (MONDO:0005365), Stickler syndrome (MONDO:0019354), nonsyndromic genetic hearing loss (MONDO:0019497), Vici syndrome (MONDO:0009452), microcephaly, epilepsy, and diabetes syndrome (MONDO:0100328), VACTERL/vater association (MONDO:0008642), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), hearing loss, autosomal recessive (MONDO:0019588), gastric cancer (MONDO:0001056), Fuchs’ endothelial dystrophy (MONDO:0005321)

Orphanet (8): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Stickler syndrome (Orphanet:828), Rare non-syndromic genetic deafness (Orphanet:87884), Rare genetic deafness (Orphanet:96210), Vici syndrome (Orphanet:1493), Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome (Orphanet:306558), VACTERL/VATER association (Orphanet:887), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000360	Tinnitus
HP:0001751	Abnormal vestibular function
HP:0008619	Bilateral sensorineural hearing impairment

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004286_10	Midgestational circulating levels of PBDEs (fetal genetic effect)	3.000000e-07
GCST004286_11	Midgestational circulating levels of PBDEs (fetal genetic effect)	7.000000e-06
GCST004286_9	Midgestational circulating levels of PBDEs (fetal genetic effect)	5.000000e-08
GCST006991_3	Cerebrospinal fluid t-tau levels in Alzheimer’s disease dementia	2.000000e-07
GCST007012_5	Cerebrospinal fluid AB1-42 levels	1.000000e-07
GCST012442_22	Age-related hearing impairment	2.000000e-22

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007959	fetal genotype effect measurement
EFO:0007961	polybrominated biphenyl measurement
EFO:0007962	polybrominated diphenyl ether measurement
EFO:0007964	gestational serum measurement
EFO:0004760	t-tau measurement
EFO:0004670	beta-amyloid 1-42 measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D005642	Fuchs’ Endothelial Dystrophy	C11.204.236.438; C11.270.162.438; C16.320.290.162.410
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C535566	Absent corpus callosum cataract immunodeficiency (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C567543	Deafness, Autosomal Recessive 77 (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

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, affects methylation, decreases methylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Fulvestrant	affects methylation, affects cotreatment	1
Air Pollutants	affects methylation, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cannabinoids	affects methylation, increases abundance	1
Copper	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Particulate Matter	affects methylation, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00781027	PHASE4	COMPLETED	Fuchs’ Torsional Phaco Study
NCT03249337	PHASE4	RECRUITING	Glanatec(R) for Descemet Stripping in Fuch’s Endothelial Dystrophy
NCT05716945	PHASE4	RECRUITING	The OPTIMISE Study
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
NCT03248037	PHASE3	COMPLETED	Trial of Netarsudil for Prevention of Corticosteroid-induced Intraocular Pressure Elevation
NCT05275972	PHASE3	RECRUITING	Descemet Endothelial Thickness Comparison Trial II
NCT06048380	PHASE3	RECRUITING	The Effects of Ripasudil in Patients With FED Undergoing Femtosecond Laser Assisted Cataract Surgery
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
NCT02834260	PHASE2	COMPLETED	Immunosuppression During Penetrating Keratoplasty, Using a Subconjunctival Implant Releasing Dexamethasone : Tolerance and Safety Pilot Study
NCT03575130	PHASE2	UNKNOWN	Ripasudil 0.4% Eye Drops in Fuchs Endothelial Corneal Dystrophy
NCT03813056	PHASE2	UNKNOWN	Ripasudil for Enhanced Corneal Clearing Following Descemet Membrane Endothelial Keratoplasty in Fuchs’ Dystrophy
NCT04676737	PHASE2	COMPLETED	TTHX1114(NM141) in Combination With DWEK/DSO
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
NCT04191629	PHASE1	UNKNOWN	Phase 1 Study to Evaluate the Safety and Tolerability of EO1404 in the Treatment of Corneal Edema
NCT04319848	PHASE1	RECRUITING	Safety and Efficacy of Tissue Engineered Endothelial Keratoplasty
NCT05636579	PHASE1	RECRUITING	Study to Assess Safety and Tolerability of Multiple Doses of EO2002
NCT07325097	PHASE1	RECRUITING	PVEK Corneal Implant For Treatment of Corneal Edema
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