rs554847663
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001292063.2(OTOG):c.2464C>T(p.Gln822*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,526,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
OTOG
NM_001292063.2 stop_gained
NM_001292063.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.54
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-17574890-C-T is Pathogenic according to our data. Variant chr11-17574890-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17574890-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000361 AC: 55AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000384 AC: 49AN: 127718Hom.: 0 AF XY: 0.000413 AC XY: 28AN XY: 67734
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GnomAD4 exome AF: 0.000410 AC: 563AN: 1374426Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 299AN XY: 674970
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GnomAD4 genome 0.000361 AC: 55AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74374
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 18B Pathogenic:5
| Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 19, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 24, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 26, 2022 | This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PM3_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 22, 2021 | ACMG codes:PVS1, PM2, PP5 - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2023 | This sequence change creates a premature translational stop signal (p.Gln834*) 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 (rs554847663, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 29907799). ClinVar contains an entry for this variant (Variation ID: 417941). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2024 | Nonsense 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: 10655058, 29907799, 32860223, 33105617, 34426522, 36147510, 34515852) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | OTOG: PVS1, PM2 - |
Seizure;C3714756:Intellectual disability Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Feb 07, 2019 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 14, 2020 | The p.Gln834X variant in OTOG has been identified in 4 individuals with hearing loss: 2 heterozygotes where a second variant was not identified on the other copy of OTOG, in 1 homozygote, and in 1 compound heterozygote with a second pathogenic OTOG variant (Sheppard 2018 PMID: 29907799, LMM data). Both variants segregated with hearing loss in an affected sibling (LMM data). The p.Gln834X variant has also been reported by other clinical laboratories in ClinVar (Variation ID 417941) and has been identified in 0.12% (8/6636) of Ashkenazi Jewish and in 0.08% (51/60760) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 834, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOG gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3, PP1, BS1_Supporting. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at