OTOGL

protein-coding

otogelin like

Gene summary

The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

Previous symbols:

C12orf64

MANE transcript

NM_001378609.3

Inheritance

ClinVar variants

P:108U:532B:235

Top phenotype

Deafness, autosomal recessive 84B

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr12:80,099,537-80,380,880

External References & Databases

Ensembl (ENSG00000165899)

Transcript & Mutation Effects

hg38 • Region Span ~281.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 84BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013984

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 84BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013984

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 84BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013984

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 84BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013984

Submitter: G2P

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The OTOGL gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/5/2017. This association was made using case-level data only. At least 10 variants (nonsense, frameshift, splice) have been reported in humans. OTOGL was first associated with this disease in humans as early as 2012 (Yariz et al.). Association is seen in at least 6 probands in 5 publications (23122586, 23850727, 25829320, 25719458, 28426234). Variants in this gene segregated with disease in 9 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by a zebrafish model and expression studies. In summary, OTOGL is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 84BAR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 23122586

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OTOGL variants in ClinVar

12 Conditions Cataloged

not providedTotal: 793

Inborn genetic diseasesTotal: 348

not specifiedTotal: 133

Autosomal recessive nonsyndromic hearing loss 84BTotal: 84

OTOGL-related disorderTotal: 69

Rare genetic deafnessTotal: 19

Meniere diseaseTotal: 5

Hearing impairmentTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378609.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	10 clinvar	152 clinvar	13 clinvar	177
missense		3 clinvar	517 clinvar	56 clinvar	14 clinvar	590
nonsense	21 clinvar	19 clinvar	4 clinvar			44
start loss						0
frameshift	18 clinvar	23 clinvar				41
splice donor/acceptor (+/-2bp)	2 clinvar	20 clinvar	1 clinvar			23
Total	41	67	532	208	27	875

Highest pathogenic variant AF is 0.00016489452

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378609.3	RefSeq	NP_001365538.2	58	MANE Select
ENST00000547103.7	Ensembl	ENSP00000447211.2	58	MANE Select
NM_001368062.3	RefSeq	NP_001354991.2	57	Standard
NM_001378610.3	RefSeq	NP_001365539.2	58	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
otogl	Danio rerio	Structure: sagitta Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

otogl

Danio rerio

Structure: sagitta

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
L-arabinose metabolic process

Molecular Function

alpha-L-arabinofuranosidase activity

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000458043
Coding exons: 58
Length: 169638
Individuals with no LoFs: 124004
Homozygous LoFs: 2
Heterozygous LoFs: 369
Defined: 124375
p: 0.00149

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.578	1059	1.11e+3	0.951	0.0000543	15358
Missense (PolyPhen)		422	443.79	0.9509		6119
Synonymous	0.422	373	384	0.973	0.0000198	4033
Loss of Function	2.51	97	128	0.760	0.00000673	1760

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.00092	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.0021	0.0021	notable
East Asian	0.0019	0.0018	notable
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.0020	0.0019	notable
South Asian	0.0013	0.0012	notable
Other	0.0017	0.0016	notable

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0917

Essentials

Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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