ClinVar Genomic variation as it relates to human health
NM_144672.4(OTOA):c.2359G>T (p.Glu787Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(3); Likely pathogenic(2); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_144672.4(OTOA):c.2359G>T (p.Glu787Ter)
Variation ID: 218841 Accession: VCV000218841.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 21736318 (GRCh38) [ NCBI UCSC ] 16: 21747639 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 27, 2015 Nov 4, 2023 Sep 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_144672.4:c.2359G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_653273.3:p.Glu787Ter nonsense NM_001161683.2:c.2122G>T NP_001155155.1:p.Glu708Ter nonsense NM_144672.3:c.[2359G>T] NM_170664.3:c.1387G>T NP_733764.1:p.Glu463Ter nonsense NC_000016.10:g.21736318G>T NC_000016.9:g.21747639G>T NG_012973.2:g.77186G>T - Protein change
- E787*, E463*, E708*
- Other names
- p.Glu787X
- Canonical SPDI
- NC_000016.10:21736317:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00122
The Genome Aggregation Database (gnomAD) 0.00927
1000 Genomes Project 30x 0.06168
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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OTOA | - | - |
GRCh38 GRCh38 GRCh37 |
642 | 760 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2020 | RCV000202954.4 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Sep 26, 2023 | RCV000764038.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2019 | RCV000825538.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 05, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000258245.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 22
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894992.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Jan 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966854.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.2359G>T, p.Glu787X variant in OTOA is a nonsense variant leads to a premat ure termination codon at position 787, which is predicted to lead … (more)
The c.2359G>T, p.Glu787X variant in OTOA is a nonsense variant leads to a premat ure termination codon at position 787, which is predicted to lead to a truncated or absent protein. Of note, the OTOA gene has a pseudogene (OTOAP1, loc653786) that contains this nucleotide variant as the reference base (GrCH37 chr16:225637 62) in humans. As such, the p.Glu787X variant requires long range PCR to determ ine whether the variant exists in the OTOA or OTOAP1 gene. This variant has been identified in 1 individual by our laboratory who harbored a deletion of the OTO A gene on the remaining allele, and the p.Glu787X variant was confirmed by long range PCR in both the proband and an unaffected parent. Furthermore, the varian t has been previously reported in 1 individual with hearing loss and in the hete rozygous state in 1 healthy individual (Guo 2013, Lindor 2015); however, it is n ot clear if these studies performed long range PCR to distinguish between the ge ne and pseudogene. This variant has also been reported in 1% (165/16068) of East Asian chromosomes by gnomAD; however, it failed the sequencing quality metric f ilter in this database and thus contamination from the pseudogene cannot be rule d out for those individuals (http://gnomad.broadinstitute.org). As such, the pop ulation frequency of this variant is unknown. Loss of function of the OTOA gene is an established disease mechanism in autosomal recessive hearing loss. In summ ary, although additional studies are required to fully establish its clinical si gnificance, this variant meets criteria to be classified as likely pathogenic fo r autosomal recessive hearing loss, provided that it is confirmed to be present in the OTOA gene and not the OTOAP1 pseudogene. ACMG/AMP Criteria applied: PVS1, PM3. (less)
Number of individuals with the variant: 2
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Uncertain significance
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251815.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(Jan 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 22
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984642.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 22
Affected status: yes
Allele origin:
biparental
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001994816.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 22
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073146.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The stop gained p.E787* in OTOA (NM_144672.4) has been previously reported in affected individuals (Lindor et al, 2015). The variant is present in OTOP which … (more)
The stop gained p.E787* in OTOA (NM_144672.4) has been previously reported in affected individuals (Lindor et al, 2015). The variant is present in OTOP which overlaps with a pseudogene and hence currently without confirmation via long rage PCR and sanger it is not possible to predict if the variant arises from the gene or pseudogene. The variant is present in gnomAD database but has been flagged as having low sequencing quality and may not represent true frequency. The variant has been submitted to ClinVar as Likey Pathogenic/ Uncertain significance. If confirmed to be present in the gene OTOA, it is predicted to cause protein truncation. Loss of function variants have been previousy reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Abnormality of the gastrointestinal tract (present) , Constipation (present)
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Pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 22
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100193.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: OTOA c.2359G>T (p.Glu787X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: OTOA c.2359G>T (p.Glu787X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00031 in 243820 control chromosomes (gnomAD). c.2359G>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss or unilateral auditory neuropathy (van Beeck Calkoen_2019, Song_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34175691, 31152317). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical characteristics of patients with unilateral auditory neuropathy. | Song M | American journal of otolaryngology | 2021 | PMID: 34175691 |
The etiological evaluation of sensorineural hearing loss in children. | van Beeck Calkoen EA | European journal of pediatrics | 2019 | PMID: 31152317 |
Whole-Exome Sequencing of 10 Scientists: Evaluation of the Process and Outcomes. | Lindor NM | Mayo Clinic proceedings | 2015 | PMID: 26434960 |
Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family. | Gao X | PloS one | 2013 | PMID: 23690975 |
Text-mined citations for rs200988634 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.