rs751127167

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001292063.2(OTOG):c.499delG(p.Val167TrpfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,458,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.08

Publications

0 publications found

Variant links:

Genes affected

OTOG (HGNC:8516): (otogelin) 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]

OTOG Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-17553476-TG-T is Pathogenic according to our data. Variant chr11-17553476-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.499delG	p.Val167TrpfsTer53	frameshift_variant	Exon 6 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.535delG	p.Val179TrpfsTer53	frameshift_variant	Exon 5 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.499delG	p.Val167TrpfsTer53	frameshift_variant	Exon 6 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.535delG	p.Val179TrpfsTer53	frameshift_variant	Exon 5 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000498332.5 link	n.405delG		non_coding_transcript_exon_variant	Exon 5 of 16	5
OTOG	ENST00000428619.1 link	c.*33delG		downstream_gene_variant		3		ENSP00000399057.2	C9IZ84

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000103

AC:

AN:

77876

AF XY:

0.0000764

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1305952

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

634020

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

28512

American (AMR)

AF:

0.0000484

AC:

AN:

20674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

34660

South Asian (SAS)

AF:

0.00

AC:

AN:

63254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.00000193

AC:

AN:

1035238

Other (OTH)

AF:

0.0000370

AC:

AN:

53984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000335

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000355

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a second variant, phase unknown, in a patient with severe-profound bilateral sensorineural hearing loss in the published literature (PMID: 36515421); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 36147510, 36515421) -

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val179Trpfs*53) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (rs751127167, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 228284). For these reasons, this variant has been classified as Pathogenic. -

May 23, 2018

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rare genetic deafness

Pathogenic:1

Feb 04, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Val179fs variant in OTOG has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/722 of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); h owever, this frequency is low enough to be consistent with a recessive carrier f requency. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 179 and leads to a premature ter mination codon 53 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of Otog in mice resulted in deafness supporting of a los s-of-function mechanism for the disease (Simmler 2000). While these two studies provide evidence of a causative link between loss of function of OTOG and autoso mal recessive hearing loss, to date, no other publications report on OTOG varian ts in individuals with hearing loss. In summary, although additional evidence is required to strengthen the gene-disease association for OTOG and hearing loss, the current data supports a likely pathogenic role for the p.Val179fs variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over