OTOG

protein-coding

otogelin

Gene summary

The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

MANE transcript

NM_001292063.2

Inheritance

ClinVar variants

P:141U:539B:423

Top phenotype

Deafness, autosomal recessive 18B

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr11:17,547,259-17,647,150

External References & Databases

Ensembl (ENSG00000188162)

Transcript & Mutation Effects

hg38 • Region Span ~99.9 kb

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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

The OTOG gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/28/2017. This association was made using case-level data only. At least 3 variants (missense, nonsense, & frameshift) have been published in humans (23122587). Association is seen in at least 2 probands in 1 publication (23122587). Variants in this gene segregated with disease in 4 additional family members. Additionally, the Partners Laboratory for Molecular Medicine has six unpublished internal cases of probands with mild sensorineural hearing loss and homozygous or compound heterozygous loss of function variants. This gene-disease association is supported by mouse and zebrafish models and expression studies. In summary, OTOG is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 6/28/2018.

autosomal recessive nonsyndromic hearing loss 18BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013985

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive nonsyndromic hearing loss 18BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013985

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 18BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013985

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 18BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013985

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 18BAR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 23122587

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTOG variants in ClinVar

15 Conditions Cataloged

not providedTotal: 1243

not specifiedTotal: 260

Autosomal recessive nonsyndromic hearing loss 18BTotal: 124

OTOG-related disorderTotal: 118

Rare genetic deafnessTotal: 22

Meniere diseaseTotal: 12

Hearing impairmentTotal: 7

Hearing loss, autosomal recessiveTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001292063.2. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	297 clinvar	19 clinvar	326
missense	1 clinvar	7 clinvar	521 clinvar	93 clinvar	14 clinvar	636
nonsense	29 clinvar	31 clinvar	2 clinvar			62
start loss			1 clinvar			1
frameshift	19 clinvar	28 clinvar	4 clinvar			51
splice donor/acceptor (+/-2bp)	4 clinvar	22 clinvar	1 clinvar			27
Total	53	88	539	390	33	1103

Highest pathogenic variant AF is 0.0004048042

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001292063.2	RefSeq	NP_001278992.1	56	MANE Select
ENST00000399397.6	Ensembl	ENSP00000382329.2	56	MANE Select
NM_001277269.2	RefSeq	NP_001264198.1	55	Standard
ENST00000399391.7	Ensembl	ENSP00000382323.2	55	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
otog	Danio rerio	Structure: otolith Quality: increased size abnormal

Gene / Model

Organism

Observed Phenotype

otog

Danio rerio

Structure: otolith

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
adult locomotory behavior
L-arabinose metabolic process

Molecular Function

structural molecule activity
alpha-L-arabinofuranosidase activity

Cellular Component

extracellular space
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399391
Coding exons: 55
Length: 99778
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	1413	1.63e+3	0.866	0.0000986	18693
Missense (PolyPhen)		484	572.38	0.84559		6837
Synonymous	2.64	595	683	0.871	0.0000433	6070
Loss of Function	3.96	79	127	0.621	0.00000661	1495

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Glycoprotein specific to acellular membranes of the inner ear. May be required for the anchoring of the otoconial membranes and cupulae to the underlying neuroepithelia in the vestibule. May be involved in the organization and/or stabilization of the fibrillar network that compose the tectorial membrane in the cochlea. May play a role in mechanotransduction processes (By similarity). {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 18B (DFNB18B) [MIM:614945]: A form of non-syndromic deafness characterized by a moderate hearing impairment, which can be associated with vestibular dysfunction, and a flat to shallow "U" or slightly downsloping shaped audiograms. {ECO:0000269|PubMed:23122587}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.130

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High