GeneBe

OTOF

protein-coding

otoferlin, the group of Ferlin family

Gene summary

Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • DFNB9

MANE transcript

NM_194248.3

Inheritance

AR

ClinVar variants

P:352U:466B:845

Top phenotype

Deafness, autosomal recessive 9; Neuropathy, autosomal recessive, 1

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr2:26,457,203-26,558,756

External References & Databases

Ensembl (ENSG00000115155)NCBI Gene (9381)OMIM (603681)HGNC:8515GenCCUniProt (Q9HC10)AlphaFoldClinVar (OTOF)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~101.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

Pathogenic variants in OTOF are associated with auditory neuropathy spectrum disorder (ANSD), a form of hearing loss characterized by defective synaptic transmission between Inner Hair Cells (IHCs) and auditory nerve fibers (PMID: 20301429). OTOF (NM_001287489.2) was first reported in relation to autosomal recessive sensorineural hearing loss (DFNB9) in 1999 (PMID: 10192385). Of note, there is another OTOF transcript, NM_194248.3, which is expressed in the brain and is not relevant to hearing. Therefore, the hearing loss evidence should be evaluated in the context of the cochlear transcript NM_001287489.2. Five variants (nonsense, missense, splice site) that have been reported in four probands in four publications (PMIDs: 10192385, 11483641, 12127154, 24135434) are included in this curation. The mechanism of pathogenicity is loss of function, as a lack of OTOF results in abolished depolarization-induced exocytosis of Ca2+ ions in IHCs (PMID: 17055430). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is also supported by an expression study showing OTOF expression in cochlear hair cells during embryonic development and postnatally (PMID: 17055430). Protein interaction studies have also indicated that OTOF interacts with MYO6, a gene that is implicated in hearing loss and controls targeting of intracellular proteins to the membrane of inner hair cells (PMID: 19417007). OTOF also interacts with syntaxin1 and SNAP25 (which are involved in synaptic vesicle exocytosis) in a Ca2+-dependent manner (PMID: 17055430). Additionally, Otof -/- mice were shown to have a decreased number of ribbon synapses in the IHCs at 15 days old and had profound hearing loss (PMID: 17055430). Another study using a pachanga mouse model demonstrated that mice with a homozygous missense variant had profound deafness (PMID: 20562868). In summary, there is definitive evidence supporting the relationship between OTOF and autosomal recessive sensorineural hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. OTOF gene therapy has demonstrated efficacy and safety across preclinical and clinical studies, culminating in a recent regulatory approval by the U.S. Food and Drug Administration (FDA). Initial clinical trials using DB-OTO (dual Adeno-Associated Virus 1 gene therapy) showed substantial functional improvement in children with OTOF-related hearing loss (PMID: 41085057). These findings were reinforced by multiple subsequent early-phase trials, which consistently demonstrated improvement in auditory thresholds and speech perception across treated participants (PMIDs: 38839897, 38280389, 40690227). Subsequently, a single-arm, multicentre trial expanded these findings to a larger and more diverse population, including a broader age range and a longer follow-up duration, further supporting the safety and sustained efficacy of AAV1-hOTOF (PMID: 42020731). Based on robust evidence, this therapy was approved by the U.S. FDA, marking a significant milestone as one of the first gene therapies for genetic hearing loss.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010986

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010986

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010986

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 9; Neuropathy, autosomal recessive, 1AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Individuals with NSRAN can have normal otoacoustic emissions test, but pure-tone audiometry/ABR will show abnormalities

Refs: 10192385; 12114484; 12525542; 16097006; 16371502; 19461658Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTOF variants in ClinVar

21 Conditions Cataloged
not providedTotal: 1848
Autosomal recessive nonsyndromic hearing loss 9Total: 405
not specifiedTotal: 308
Inborn genetic diseasesTotal: 181
OTOF-related disorderTotal: 63
Nonsyndromic genetic hearing lossTotal: 32
Rare genetic deafnessTotal: 28
Auditory neuropathyTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_194248.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
20
clinvar
629
clinvar
10
clinvar
 660
missense
13
clinvar
41
clinvar
423
clinvar
195
clinvar
10
clinvar
 682
nonsense
74
clinvar
16
clinvar
5
clinvar
1
clinvar
 96
start loss
0
frameshift
73
clinvar
39
clinvar
9
clinvar
 121
splice donor/acceptor (+/-2bp)
30
clinvar
65
clinvar
9
clinvar
 104
Total190162466825201663

Highest pathogenic variant AF is 0.000114000926

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_194248.3RefSeqNP_919224.146MANE Select
ENST00000272371.7EnsemblENSP00000272371.246MANE Select
NM_001287489.2RefSeqNP_001274418.146Standard
NM_004802.4RefSeqNP_004793.228Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
otofbDanio rerio

Structure: locomotory behavior

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • sensory perception of sound
  • synaptic vesicle exocytosis
  • membrane fusion

Molecular Function

  • molecular_function
  • calcium ion binding

Cellular Component

  • endoplasmic reticulum membrane
  • cytosol
  • integral component of membrane
  • basolateral plasma membrane
  • cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000272371
Coding exons
46
Length
101496
Individuals with no LoFs
123599
Homozygous LoFs
92
Heterozygous LoFs
2057
Defined
125748
p
0.00858
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.28812521.22e+31.020.000085113067
Missense (PolyPhen)440448.350.981384819
Synonymous-1.445505091.080.00003743877
Loss of Function2.63761050.7230.000005651174

Population LoF Frequency

PopulationCAFp-valueStatus
African0.120.090notable
Latino/Admixed American0.00800.0072notable
Ashkenazi Jewish0.00100.00099notable
East Asian0.0120.013notable
Finnish0.000420.00042rare
European (Non-Finnish)0.00190.0018notable
South Asian0.000790.00075rare
Other0.00690.0062notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes (By similarity). {ECO:0000250}.;
Disease
DISEASE: Deafness, autosomal recessive, 9 (DFNB9) [MIM:601071]: 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. {ECO:0000269|PubMed:10192385, ECO:0000269|PubMed:12127154, ECO:0000269|PubMed:16097006, ECO:0000269|PubMed:16283880, ECO:0000269|PubMed:16371502, ECO:0000269|PubMed:26437881}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Auditory neuropathy, autosomal recessive, 1 (AUNB1) [MIM:601071]: A form of sensorineural hearing loss with absent or severely abnormal auditory brainstem response, in the presence of normal cochlear outer hair cell function and normal otoacoustic emissions. Auditory neuropathies result from a lesion in the area including the inner hair cells, connections between the inner hair cells and the cochlear branch of the auditory nerve, the auditory nerve itself and auditory pathways of the brainstem. In some cases AUNB1 phenotype can be temperature sensitive. {ECO:0000269|PubMed:16371502, ECO:0000269|PubMed:18381613}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.315
RVIS EVS
-0.11
RVIS percentile EVS
45.58

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.712

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.