ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.2348del (p.Gly783fs)
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
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NM_194248.3(OTOF):c.2348del (p.Gly783fs)
Variation ID: 21834 Accession: VCV000021834.20
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26477474 (GRCh38) [ NCBI UCSC ] 2: 26700342 (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 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194248.3:c.2348del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Gly783fs frameshift NM_194248.3:c.2348delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_194323.3:c.107del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919304.1:p.Gly36fs frameshift NM_001287489.2:c.2348del NP_001274418.1:p.Gly783fs frameshift NM_004802.4:c.107del NP_004793.2:p.Gly36fs frameshift NM_194322.3:c.278del NP_919303.1:p.Gly93fs frameshift NC_000002.12:g.26477476del NC_000002.11:g.26700344del NG_009937.1:g.86225del - Protein change
- G783fs, G93fs, G36fs
- Other names
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- Canonical SPDI
- NC_000002.12:26477473:CCC:CC
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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.
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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 |
1948 | 2085 |
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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Pathogenic (2) |
criteria provided, single submitter
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Apr 22, 2022 | RCV000021046.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2015 | RCV000211837.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001730476.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV002513157.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2023 | RCV003114200.3 |
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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Pathogenic
(Feb 26, 2015)
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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: SCV000065185.6
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Comment:
The p.Gly783fs variant in OTOF has been reported in 2 siblings with auditory neu ropathy (Varga 2006) and has been identified by our laboratory in … (more)
The p.Gly783fs variant in OTOF has been reported in 2 siblings with auditory neu ropathy (Varga 2006) and has been identified by our laboratory in 1 individual w ith congenital hearing loss. All of these individuals were compound heterozygous . Data from large population studies are insufficient to assess the frequency of this variant. The p.Gly783fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 783 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant me ets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner (www.partners.org/personalizedmedicine/LMM) based upon its pre dicted impact on the protein. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jan 31, 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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Invitae
Accession: SCV003524153.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly783Alafs*17) 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.Gly783Alafs*17) 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 (rs80356591, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of OTOF-related conditions (PMID: 16371502, 31980526). ClinVar contains an entry for this variant (Variation ID: 21834). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 22, 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:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503775.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is a deletion of 1 bp in exon 20 (of 46) of OTOF that is predicted to create a premature termination codon … (more)
This sequence change is a deletion of 1 bp in exon 20 (of 46) of OTOF that is predicted to create a premature termination codon at position 799, p.(Gly783Alafs*17), which is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism for disease for this gene. The variant is present in a large population cohort at a frequency of 0.005% (rs80356591, 12/262,222 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.02% in the African subpopulation (4/22,908 alleles, 0 homozygotes). The variant has been identified compound heterozygous with a second pathogenic allele in at least two individuals with non-syndromic auditory neuropathy (PMID: 16371502, 19461658). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Bilateral sensorineural hearing impairment
Affected status: yes
Allele origin:
germline
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Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo
Accession: SCV001762958.1
First in ClinVar: Oct 21, 2021 Last updated: Oct 21, 2021 |
Comment:
in compound heterozygosis with another frameshift variant, both likely pathogenic in patient with auditory neuropathy
Clinical Features:
Prelingual sensorineural hearing impairment (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
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Pathogenic
(Jan 11, 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: SCV003801309.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: OTOF c.2348delG (p.Gly783AlafsX17) 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.2348delG (p.Gly783AlafsX17) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.2485C>T [p.Gln829Ter], c.2977_2978del [p.Gln994fs]). The variant allele was found at a frequency of 4.6e-05 in 262222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (4.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.2348delG has been reported in the literature as a biallelic genotype in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Romanos_2009, Rodriguez-Ballesteros_2008, Baux_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (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: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000041700.2
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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Genetic etiology of non-syndromic hearing loss in Latin America. | Lezirovitz K | Human genetics | 2022 | PMID: 34652575 |
OTOF-Related Deafness. | Adam MP | - | 2021 | PMID: 20301429 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients. | Baux D | Scientific reports | 2017 | PMID: 29196752 |
A prevalent founder mutation and genotype-phenotype correlations of OTOF in Japanese patients with auditory neuropathy. | Matsunaga T | Clinical genetics | 2012 | PMID: 22575033 |
Novel OTOF mutations in Brazilian patients with auditory neuropathy. | Romanos J | Journal of human genetics | 2009 | PMID: 19461658 |
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 |
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 |
Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. | Varga R | Journal of medical genetics | 2003 | PMID: 12525542 |
Text-mined citations for rs80356591 ...
HelpRecord last updated Apr 15, 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.