LHFPL5

Summary

LHFPL5 (LHFPL tetraspan subfamily member 5, HGNC:21253) is a protein-coding gene on chromosome 6p21.31, encoding LHFPL tetraspan subfamily member 5 protein (Q8TAF8). Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of the shorter stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.

This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis.

Source: NCBI Gene 222662 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 186 total — 9 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_182548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21253
Approved symbol	LHFPL5
Name	LHFPL tetraspan subfamily member 5
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	MGC33835, dJ510O8.8, Tmhs
Ensembl gene	ENSG00000197753
Ensembl biotype	protein_coding
OMIM	609427
Entrez	222662

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000360215, ENST00000496656, ENST00000651132, ENST00000651676, ENST00000651994, ENST00000652718

RefSeq mRNA: 1 — MANE Select: NM_182548 NM_182548

CCDS: CCDS4812

Canonical transcript exons

ENST00000360215 — 4 exons

Exon	Start	End
ENSE00001193148	35819437	35819463
ENSE00003651610	35814546	35814782
ENSE00003831190	35805352	35806082
ENSE00003848290	35822982	35824070

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 84.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1207 / max 41.4144, expressed in 53 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67475	0.0531	40
67476	0.0473	13
67474	0.0202	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	84.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.30	gold quality
pancreas	UBERON:0001264	76.24	gold quality
colonic epithelium	UBERON:0000397	74.60	gold quality
endothelial cell	CL:0000115	74.39	gold quality
bone marrow cell	CL:0002092	73.73	silver quality
skin of abdomen	UBERON:0001416	71.65	gold quality
skin of leg	UBERON:0001511	71.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.44	gold quality
anterior cingulate cortex	UBERON:0009835	71.13	gold quality
right frontal lobe	UBERON:0002810	70.59	gold quality
blood	UBERON:0000178	69.87	gold quality
right lung	UBERON:0002167	69.84	gold quality
cortical plate	UBERON:0005343	69.78	gold quality
prefrontal cortex	UBERON:0000451	69.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.02	gold quality
transverse colon	UBERON:0001157	68.99	gold quality
zone of skin	UBERON:0000014	68.01	gold quality
esophagus mucosa	UBERON:0002469	67.98	gold quality
stromal cell of endometrium	CL:0002255	67.73	gold quality
ectocervix	UBERON:0012249	67.73	gold quality
upper lobe of left lung	UBERON:0008952	67.42	gold quality
lower esophagus mucosa	UBERON:0035834	67.27	gold quality
rectum	UBERON:0001052	67.05	gold quality
minor salivary gland	UBERON:0001830	66.99	gold quality
spleen	UBERON:0002106	66.99	gold quality
adenohypophysis	UBERON:0002196	66.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	66.82	gold quality
buccal mucosa cell	CL:0002336	66.78	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	66.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting LHFPL5, 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-5011-5P	100.00	83.46	5820
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-17-3P	99.55	66.77	1311

Literature-anchored findings (GeneRIF, showing 12)

• The authors present an overview of the LHFP gene family in mouse and humans (PMID:15905332)
• These findings establish the importance of TMHS for normal sound transduction in humans. (PMID:16459341)
• Flies with mutations affecting the diaphanous,forked, and CG12026/TMHS genes displayed significant reductions in the amplitude of sound-evoked potentials compared to wild-type flies (PMID:19102128)
• Five microsatellites in the 6p21.31e22.3 region and screening of the LHFPL5 gene by DNA heteroduplex analysis revealed a novel mutation (c.89dup) in one out of 129 unrelated Tunisian families with autosomal recessive nonsyndromic hearing loss. (PMID:21816241)
• LHFPL5 mutation is associated with dysequilibrium syndrome type 2 and sensorineural hearing loss. (PMID:26437881)
• These findings provide a novel function of LHFPL2 and a novel genetic basis for distal reproductive tract development; they also emphasize the importance of an additional merging phase for proper reproductive tract development. (PMID:26964900)
• two novel variants in LHFPL5, including a unique 3’-UTR splice site variant that is predicted to impact pre-mRNA splicing and regulation through an extended 3’-UTR. (PMID:30177809)
• Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693. (PMID:30298622)
• A novel LHFPL5 mutation is identified in two members of a family with hereditary hearing loss. (PMID:30476627)
• In 3 families with hearing impairment, whole exome sequencing revealed 3 novel variants in KCNQ4, LHFPL5 and COCH genes. The homozygous variant (c.34A>T, p.K12X) was identified in the LHFPL5 gene (DFNB67) which encodes a transmembrane protein. (PMID:31126177)
• Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. (PMID:33168709)
• Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5. (PMID:37837560)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhfpl5a	ENSDARG00000045023
danio_rerio	lhfpl5b	ENSDARG00000056458
mus_musculus	Lhfpl5	ENSMUSG00000062252
rattus_norvegicus	Lhfpl5	ENSRNOG00000022283
drosophila_melanogaster	Tmhs	FBGN0262624

Paralogs (6): LHFPL2 (ENSG00000145685), LHFPL4 (ENSG00000156959), LHFPL1 (ENSG00000182508), LHFPL6 (ENSG00000183722), LHFPL3 (ENSG00000187416), LHFPL7 (ENSG00000206069)

Protein

Protein identifiers

LHFPL tetraspan subfamily member 5 protein — Q8TAF8 (reviewed: Q8TAF8)

Alternative names: Lipoma HMGIC fusion partner-like 5 protein, Tetraspan membrane protein of hair cell stereocilia

All UniProt accessions (3): A0A494BZZ7, A0A494C136, Q8TAF8

UniProt curated annotations — full annotation on UniProt →

Function. Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of the shorter stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system. The MET complex is composed of two dimeric pore-forming ion-conducting transmembrane TMC (TMC1 or TMC2) subunits, and aided by several auxiliary proteins including LHFPL5, TMIE, CIB2/3 and TOMT, and the tip-link PCDH15. Functionally couples PCDH15 to the transduction channel.

Subunit / interactions. Forms the MET channel composed of TMC (TMC1 or TMC2), TMIE, TOMT, CIB (CIB2 or CIB3), LHPL5 and PCDH15. Interaction with PCDH15 is required for efficient localization to hair bundles.

Subcellular location. Cell membrane.

Disease relevance. Deafness, autosomal recessive, 67 (DFNB67) [MIM:610265] 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.

Similarity. Belongs to the LHFP family.

RefSeq proteins (1): NP_872354* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019372	LHFPL	Family

Pfam: PF10242

UniProt features (15 total): topological domain 5, sequence variant 4, transmembrane region 4, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TAF8-F1	89.11	0.67

Function

Pathways and Gene Ontology

Reactome pathways

4 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
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 105 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_NEUROGENESIS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_EAR_MORPHOGENESIS, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_AUDITORY_RECEPTOR_CELL_DEVELOPMENT, GOBP_MECHANORECEPTOR_DIFFERENTIATION, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION_OF_SOUND

GO Biological Process (5): monoatomic ion transport (GO:0006811), sensory perception of sound (GO:0007605), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), detection of mechanical stimulus involved in sensory perception (GO:0050974), auditory receptor cell stereocilium organization (GO:0060088)

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

GO Cellular Component (5): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), stereocilium tip (GO:0032426), membrane (GO:0016020), stereocilium bundle (GO:0032421)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	2
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	2
stereocilium	2
cellular anatomical structure	2
transport	1
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
sensory perception	1
detection of stimulus involved in sensory perception	1
detection of mechanical stimulus	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
binding	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
cluster of actin-based cell projections	1

Protein interactions and networks

STRING

624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHFPL5	TMC1	Q8TDI8	995
LHFPL5	TMIE	Q8NEW7	984
LHFPL5	TMC2	Q8TDI7	981
LHFPL5	PCDH15	Q96QU1	954
LHFPL5	CIB2	O75838	936
LHFPL5	COL11A2	P13942	856
LHFPL5	E9PNW1	E9PNW1	786
LHFPL5	CDH23	Q9H251	728
LHFPL5	MYO7A	P78427	727
LHFPL5	STRC	Q7RTU9	678
LHFPL5	ADGRV1	Q8WXG9	648
LHFPL5	MYO15A	Q9UKN7	641
LHFPL5	WHRN	Q9P202	639
LHFPL5	PIEZO2	Q9H5I5	639
LHFPL5	BAK1	Q16611	635

IntAct

399 interactions, top by confidence:

A	B	Type	Score
GGT7	LHFPL5	psi-mi:“MI:0915”(physical association)	0.890
LHFPL5	GGT7	psi-mi:“MI:0915”(physical association)	0.890
KASH5	LHFPL5	psi-mi:“MI:0915”(physical association)	0.810
LHFPL5	KASH5	psi-mi:“MI:0915”(physical association)	0.810
LHFPL5	CREB3	psi-mi:“MI:0915”(physical association)	0.670
SLC35A1	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
CYB561	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
NKG7	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
SMIM1	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
FXYD6	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TSPAN33	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
LHFPL5	AQP6	psi-mi:“MI:0915”(physical association)	0.560
CLDND2	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
NRAC	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (146): LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), CCDC155 (Two-hybrid), CREB3 (Two-hybrid), GGT7 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid), LHFPL5 (Two-hybrid)

ESM2 similar proteins: A5A6N6, D3ZQJ0, F1QIK8, O09117, O35912, O88662, P19075, P47801, P54848, P54849, P54850, P54851, P54852, P56748, Q12999, Q16563, Q2NKU9, Q32KP1, Q3ZBY0, Q4KL25, Q58DR6, Q5PPI7, Q5R9S6, Q5RAI2, Q5RAP8, Q5RCY3, Q5U1V9, Q5XHG6, Q66HH2, Q66IV3, Q6DHB5, Q6GPN9, Q6P742, Q6Y1E2, Q6ZUX7, Q7ZUB3, Q7ZWW7, Q7ZZL8, Q8BGA2, Q8BI08

Diamond homologs: Q17R16, Q4KL25, Q5PPI7, Q5U4E0, Q66IV3, Q6DHB5, Q7TSY2, Q7Z7J7, Q7ZZL8, Q86UP9, Q8TAF8, Q9CTN8, Q5BJS2, Q8BM86, Q9Y693

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LHFPL5	“up-regulates activity”	“Hair cells mechanotransduction channel”	binding
“TIP-LINK complex”	“up-regulates activity”	LHFPL5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 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
Gap junction assembly	5	27.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	9
Uncertain significance	115
Likely benign	27
Benign	12

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1185612	NM_182548.4(LHFPL5):c.462_472dup (p.Arg158fs)	Pathogenic
1334122	NM_182548.4(LHFPL5):c.*16+1G>A	Pathogenic
1694	NM_182548.4(LHFPL5):c.250del (p.Pro83_Leu84insTer)	Pathogenic
3366908	NM_182548.4(LHFPL5):c.185del (p.Phe62fs)	Pathogenic
3601192	NM_182548.4(LHFPL5):c.396G>A (p.Trp132Ter)	Pathogenic
3601194	NM_182548.4(LHFPL5):c.650-2A>G	Pathogenic
3626351	NM_182548.4(LHFPL5):c.222del (p.Ser75fs)	Pathogenic
3687033	NM_182548.4(LHFPL5):c.219_223del (p.Ser74fs)	Pathogenic
375705	NM_182548.4(LHFPL5):c.575T>C (p.Leu192Pro)	Pathogenic
1064882	NM_182548.4(LHFPL5):c.504C>G (p.Tyr168Ter)	Likely pathogenic
1695	NM_182548.4(LHFPL5):c.380A>G (p.Tyr127Cys)	Likely pathogenic
3340152	NM_182548.4(LHFPL5):c.526C>T (p.Arg176Cys)	Likely pathogenic
3375483	NM_182548.4(LHFPL5):c.300del (p.Phe100fs)	Likely pathogenic
3601191	NM_182548.4(LHFPL5):c.200A>G (p.Tyr67Cys)	Likely pathogenic
3601193	NM_182548.4(LHFPL5):c.53A>G (p.Tyr18Cys)	Likely pathogenic
4533399	NM_182548.4(LHFPL5):c.649G>A (p.Glu217Lys)	Likely pathogenic
4813858	NM_182548.4(LHFPL5):c.34A>T (p.Lys12Ter)	Likely pathogenic
667378	NM_182548.4(LHFPL5):c.89dup (p.Thr31fs)	Likely pathogenic

SpliceAI

974 predictions. Top by Δscore:

Variant	Effect	Δscore
6:35806079:GCGG:G	donor_gain	1.0000
6:35806080:CGGGT:C	donor_loss	1.0000
6:35806082:GGTAA:G	donor_loss	1.0000
6:35806083:G:GG	donor_gain	1.0000
6:35806083:GTA:G	donor_loss	1.0000
6:35806084:T:G	donor_loss	1.0000
6:35842530:CTCA:C	donor_loss	1.0000
6:35842531:TCACC:T	donor_loss	1.0000
6:35842532:CACCT:C	donor_loss	1.0000
6:35842533:A:AT	donor_loss	1.0000
6:35842534:C:A	donor_loss	1.0000
6:35842602:GGCC:G	acceptor_loss	1.0000
6:35842603:GCC:G	acceptor_loss	1.0000
6:35842604:CCTAA:C	acceptor_loss	1.0000
6:35842605:C:CC	acceptor_gain	1.0000
6:35842605:CTAAA:C	acceptor_loss	1.0000
6:35842606:T:A	acceptor_loss	1.0000
6:35806081:GG:G	donor_gain	0.9900
6:35806082:GG:G	donor_gain	0.9900
6:35814544:A:AG	acceptor_gain	0.9900
6:35814545:G:GG	acceptor_gain	0.9900
6:35814781:CGG:C	donor_loss	0.9900
6:35814783:G:C	donor_loss	0.9900
6:35814783:G:GG	donor_gain	0.9900
6:35814784:T:A	donor_loss	0.9900
6:35838450:A:T	acceptor_gain	0.9900
6:35842528:GACTC:G	donor_loss	0.9900
6:35842529:ACTCA:A	donor_loss	0.9900
6:35842533:A:AC	donor_gain	0.9900
6:35842534:C:CC	donor_gain	0.9900

AlphaMissense

1433 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:35805755:T:A	W29R	0.999
6:35805755:T:C	W29R	0.999
6:35814587:T:A	W152R	0.999
6:35814587:T:C	W152R	0.999
6:35814589:G:C	W152C	0.999
6:35814589:G:T	W152C	0.999
6:35814652:C:G	C173W	0.999
6:35805815:T:A	W49R	0.998
6:35805815:T:C	W49R	0.998
6:35805817:G:C	W49C	0.998
6:35805817:G:T	W49C	0.998
6:35805874:C:G	C68W	0.998
6:35814575:T:G	Y148D	0.998
6:35814614:T:A	C161S	0.998
6:35814615:G:C	C161S	0.998
6:35814650:T:A	C173S	0.998
6:35814650:T:C	C173R	0.998
6:35814651:G:A	C173Y	0.998
6:35814651:G:C	C173S	0.998
6:35805822:G:A	G51D	0.997
6:35805849:G:A	G60D	0.997
6:35805857:G:C	G63R	0.997
6:35805858:G:A	G63D	0.997
6:35805858:G:T	G63V	0.997
6:35805873:G:A	C68Y	0.997
6:35805905:T:A	C79S	0.997
6:35805906:G:C	C79S	0.997
6:35814563:G:C	G144R	0.997
6:35814566:T:C	C145R	0.997
6:35814584:G:C	G151R	0.997

dbSNP variants (sampled 300 via entrez): RS1000026751 (6:35823403 A>G), RS1000036181 (6:35810482 C>G,T), RS1000228896 (6:35823557 G>A), RS1000371367 (6:35805121 C>T), RS1000528813 (6:35810841 A>G), RS1000643425 (6:35811058 G>A,C), RS1000696295 (6:35806604 C>A,T), RS1000705778 (6:35811236 A>G), RS1001298768 (6:35824266 G>A), RS1001309188 (6:35812986 C>T), RS1001340463 (6:35808956 C>T), RS1001380947 (6:35810106 G>C), RS1001580150 (6:35810214 T>C), RS1001628191 (6:35822432 T>C), RS1001687852 (6:35804172 T>G)

Disease associations

OMIM: gene MIM:609427 | disease phenotypes: MIM:610265, MIM:220290, MIM:607197, MIM:128600, MIM:256040, MIM:249500

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 67	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (7): hearing loss disorder (MONDO:0005365), autosomal recessive nonsyndromic hearing loss 67 (MONDO:0012460), hearing loss, autosomal recessive (MONDO:0019588), ear malformation (MONDO:0007500), proteasome-associated autoinflammatory syndrome 1 (MONDO:0054698), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (9): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Nakajo-Nishimura syndrome (Orphanet:2615), Proteasome-associated autoinflammatory syndrome (Orphanet:324977), JMP syndrome (Orphanet:324999), CANDLE syndrome (Orphanet:325004), Rare non-syndromic genetic deafness (Orphanet:87884), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001098	Abnormal fundus morphology
HP:0001751	Abnormal vestibular function
HP:0003577	Congenital onset
HP:0008619	Bilateral sensorineural hearing impairment

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST90002381_435	Eosinophil count	5.000000e-14
GCST90002382_342	Eosinophil percentage of white cells	4.000000e-09
GCST90002385_557	High light scatter reticulocyte count	1.000000e-10
GCST90002386_141	High light scatter reticulocyte percentage of red cells	2.000000e-13
GCST90002387_281	Immature fraction of reticulocytes	1.000000e-17
GCST90020028_590	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007986	reticulocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564609	Deafness, Autosomal Recessive (supp.)
C565207	Deafness, Autosomal Recessive 67 (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

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Copper	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

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