ClinVar Genomic variation as it relates to human health
NM_144672.4(OTOA):c.828del (p.Ser277fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_144672.4(OTOA):c.828del (p.Ser277fs)
Variation ID: 402235 Accession: VCV000402235.9
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 16p12.2 16: 21697862 (GRCh38) [ NCBI UCSC ] 16: 21709183 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 3, 2017 Feb 14, 2024 Jan 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_144672.4:c.828del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_653273.3:p.Ser277fs frameshift NM_144672.4:c.828delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001161683.2:c.591del NP_001155155.1:p.Ser198fs frameshift NM_144672.3:c.828delT NC_000016.10:g.21697863del NC_000016.9:g.21709184del NG_012973.2:g.38731del - Protein change
- S198fs, S277fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:21697861:TT:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
OTOA | - | - |
GRCh38 GRCh38 GRCh37 |
643 | 761 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2022 | RCV000454262.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 5, 2016 | RCV000612240.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 13, 2023 | RCV003392258.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV003558386.1 |
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
Help
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 22
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538051.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.828delT (p.Ser277Valfs*3) frameshift variant in the OTOA gene is predicted to cause a protein termination in exon 9 (out of a total of 28 … (more)
The c.828delT (p.Ser277Valfs*3) frameshift variant in the OTOA gene is predicted to cause a protein termination in exon 9 (out of a total of 28 exons in the coding sequence). Frameshift variants as well as splice-site variants, missense variants, and whole gene deletions have been reported in this gene for affected individuals. In vivo studies have also demonstrated loss of function is likely a mechanism for disease (Lukashkin et al., 2012). This variant is reported at low frequency within the control population databases (Exome Sequencing Project [ESP] = NA, 1000 Genomes = NA, and ExAC = 0.013). In silico algorithms predict the variant is within a conserved region (GERP = 5.77). Therefore, this collective evidence supports the classification of the c.828delT (p.Ser277Valfs*3) as an autosomal recessive Likely Pathogenic variant for Deafness and Hearing loss. (less)
|
|
Pathogenic
(May 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712100.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Ser277fs variant in OTOA has not been previously reported in individuals w ith hearing loss. This variant has been identified in 9/66700 European chromosom … (more)
The p.Ser277fs variant in OTOA has not been previously reported in individuals w ith hearing loss. This variant has been identified in 9/66700 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs751447996); however, its frequency is low enough to be consistent with a r ecessive carrier frequency. This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 277 and leads to a premature termination codon 3 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function of the O TOA gene is an established disease mechanism in autosomal recessive sensorineura l hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for sensorineural hearing loss in an autosomal recessive manner based on the predicted impact of the variant. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 22
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768235.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Deafness, autosomal recessive 22 (MIM#607039 ). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 23 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four probands with hearing loss is and classified as likely pathogenic and pathogenic by diagnostic laboratories in Clinvar (PMID: 24963352, 27068579). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Jan 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
OTOA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120469.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The OTOA c.828delT variant is predicted to result in a frameshift and premature protein termination (p.Ser277Valfs*3). This variant has been reported as pathogenic in patients … (more)
The OTOA c.828delT variant is predicted to result in a frameshift and premature protein termination (p.Ser277Valfs*3). This variant has been reported as pathogenic in patients with non-syndromic hearing loss (described as c.590delT, Table S2, Shearer et al. 2014. PubMed ID: 24963352; described as c.591delT, Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-21709182-AT-A). Frameshift variants in OTOA are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV004297683.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser277Valfs*3) in the OTOA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ser277Valfs*3) in the OTOA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOA are known to be pathogenic (PMID: 11972037). This variant is present in population databases (rs751447996, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of OTOA-related conditions (PMID: 26969326, 33879512). This variant is also known as c.591delT. ClinVar contains an entry for this variant (Variation ID: 402235). For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders. | Molina-Ramírez LP | Journal of medical genetics | 2022 | PMID: 33879512 |
DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System. | Sommen M | Human mutation | 2016 | PMID: 27068579 |
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
Copy number variants are a common cause of non-syndromic hearing loss. | Shearer AE | Genome medicine | 2014 | PMID: 24963352 |
Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. | Zwaenepoel I | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11972037 |
Text-mined citations for rs751447996 ...
HelpRecord last updated Mar 11, 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.