ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)
Variation ID: 6137 Accession: VCV000006137.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26477210 (GRCh38) [ NCBI UCSC ] 2: 26700078 (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 Apr 4, 2013 Feb 14, 2024 May 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194248.3:c.2485C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Gln829Ter nonsense NM_194323.3:c.244C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919304.1:p.Gln82Ter nonsense NM_001287489.2:c.2485C>T NP_001274418.1:p.Gln829Ter nonsense NM_004802.4:c.244C>T NP_004793.2:p.Gln82Ter nonsense NM_194322.3:c.415C>T NP_919303.1:p.Gln139Ter nonsense NC_000002.12:g.26477210G>A NC_000002.11:g.26700078G>A NG_009937.1:g.86489C>T - Protein change
- Q829*, Q139*, Q82*
- Other names
- NM_194248.3(OTOF):c.2485C>T
- Canonical SPDI
- NC_000002.12:26477209:G:A
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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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0.00040 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00017
Exome Aggregation Consortium (ExAC) 0.00020
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
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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OTOF | - | - |
GRCh38 GRCh37 |
1975 | 2113 |
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
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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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Pathogenic (3) |
criteria provided, single submitter
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Dec 5, 2022 | RCV000006511.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2019 | RCV000211838.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000325939.18 | |
Pathogenic (2) |
reviewed by expert panel
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May 13, 2022 | RCV002227998.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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. |
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Pathogenic
(May 13, 2022)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002512132.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for … (more)
The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for Latino chromosomes in gnomAD v2.1.1, which meets the cutoff to apply BS1_Supporting. However, this variant has been established as a founder variant in the Spanish population and is thought to be causative in 3% of cases of deafness in the Spanish population (BS1_Supporting not applicable; PMID: 27177047). The p.Gln829Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 21/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID: 30192042). The p.Gln829Ter variant has been identified in >50 patients with non-syndromic hearing loss (PM3_VeryStrong; PMIDs: 18381613, 17036997, 16371502, 14635104, 12114484). It has repeatedly been reported to segregate with hearing loss (PP1_Strong; PMIDs: 12114484, 14635104,16371502, 18381613). In addition to hearing loss, at least 24 patients reported to have the p.Gln829Ter variant presented with features of auditory neuropathy spectrum disorder, which is highly specific to OTOF and autosomal recessive hearing loss (PP4; PMIDs:18381613, 17036997, 14635104). In summary, the p.Gln829Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PP1_Strong, PM3_VeryStrong, PP4. (less)
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Pathogenic
(Mar 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065196.7
First in ClinVar: May 03, 2013 Last updated: Jul 06, 2020 |
Comment:
The p.Gln829X variant in OTOF has been previously reported in >30 individuals with hearing loss or auditory neuropathy, all of whom were homozygous or compound … (more)
The p.Gln829X variant in OTOF has been previously reported in >30 individuals with hearing loss or auditory neuropathy, all of whom were homozygous or compound heterozygous for a second pathogenic OTOF variant, and segregated in >10 affected relatives (Migliosi 2002, Rodriguez-Ballesteros 2003, Rodriguez-Ballesteros 2008, Varga 2006). This variant has been identified in 0.06% (22/34228) of Latino chromosomes by gnomAD, and has been reported to be a founder variant in the Spanish population based on linkage data (Migliosi 2002; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 829, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOF gene is an established disease mechanism in autosomal recessive auditory neuropathy spectrum disorder. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive auditory neuropathy spectrum disorder. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting. (less)
Number of individuals with the variant: 10
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Pathogenic
(Oct 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329902.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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: 16226319, 12114484, 25525159, 16371502, 31589614, 18381613, 14635104, 17036997, 31980526, 27177047, 33297549) (less)
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Pathogenic
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004222718.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: OTOF c.2485C>T (p.Gln829X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: OTOF c.2485C>T (p.Gln829X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00017 in 243966 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00017 vs 0.0011), allowing no conclusion about variant significance. c.2485C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Rodriguez-Ballesteros_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18381613). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001587436.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln829*) in the OTOF gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln829*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs80356593, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with non-syndromic, prelingual sensorineural hearing loss (PMID: 12114484, 14635104, 16226319, 16371502, 17036997, 18381613). It is commonly reported in individuals of Spanish ancestry (PMID: 18381613). ClinVar contains an entry for this variant (Variation ID: 6137). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503161.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 9
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835879.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jul 01, 2006)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 9
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026694.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2018 |
Comment on evidence:
Among 28 unrelated Spanish families with nonsyndromic sensorineural hearing loss (601071), Migliosi et al. (2002) identified 1 family with a mutation in the OTOF gene: … (more)
Among 28 unrelated Spanish families with nonsyndromic sensorineural hearing loss (601071), Migliosi et al. (2002) identified 1 family with a mutation in the OTOF gene: a 2485C-T transition in exon 22, resulting in a premature stop codon, gln829 to ter (Q829X). Both parents were carriers of the mutation and their 2 affected children were homozygous. The mutation was not present in 200 unrelated Spanish controls with normal hearing. Genetic analysis of another 269 unrelated patients with hearing loss revealed 11 more cases (8 sporadic and 3 familial) of the Q829X mutation. One of these families was compound heterozygous for Q829X and P1825A (603681.0005). Migliosi et al. (2002) determined that the Q829X mutation was responsible for 4.4% of recessive familial or sporadic cases of deafness in the Spanish population, and presented evidence for a founder effect. Varga et al. (2006) found the Q829X mutation in 2 families. They referred to Q829X as the Hispanic mutation, it having been found in a group of Spanish families and 1 Cuban family as noted. They described it in a family from England with no known Hispanic ancestry. In a family of Mexican ancestry, the Q829X mutation was present in heterozygous state. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive nonsyndromic hearing loss 9
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000041704.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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OTOF-Related Deafness. | Adam MP | - | 2021 | PMID: 20301429 |
Molecular study of patients with auditory neuropathy. | Carvalho GM | Molecular medicine reports | 2016 | PMID: 27177047 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
A prevalent founder mutation and genotype-phenotype correlations of OTOF in Japanese patients with auditory neuropathy. | Matsunaga T | Clinical genetics | 2012 | PMID: 22575033 |
Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. | Choi BY | Clinical genetics | 2009 | PMID: 19250381 |
A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy. | Rodríguez-Ballesteros M | Human mutation | 2008 | PMID: 18381613 |
[Auditory neuropathy due to the Q829X mutation in the gene encoding otoferlin (OTOF) in an infant screened for newborn hearing impairment]. | Gallo-Terán J | Acta otorrinolaringologica espanola | 2006 | PMID: 17036997 |
OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele. | Varga R | Journal of medical genetics | 2006 | PMID: 16371502 |
Results of cochlear implantation in two children with mutations in the OTOF gene. | Rouillon I | International journal of pediatric otorhinolaryngology | 2006 | PMID: 16226319 |
Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). | Rodríguez-Ballesteros M | Human mutation | 2003 | PMID: 14635104 |
Q829X, a novel mutation in the gene encoding otoferlin (OTOF), is frequently found in Spanish patients with prelingual non-syndromic hearing loss. | Migliosi V | Journal of medical genetics | 2002 | PMID: 12114484 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fd96b31f-e928-4d10-85de-65170a3b6d72 | - | - | - | - |
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Text-mined citations for rs80356593 ...
HelpRecord last updated Sep 29, 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.