ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.2239G>T (p.Glu747Ter)
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.2239G>T (p.Glu747Ter)
Variation ID: 65787 Accession: VCV000065787.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26477725 (GRCh38) [ NCBI UCSC ] 2: 26700593 (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 Oct 2, 2013 Apr 6, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194248.3:c.2239G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Glu747Ter nonsense NM_194323.3:c.-3G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NM_001287489.2:c.2239G>T NP_001274418.1:p.Glu747Ter nonsense NM_004802.4:c.-3G>T 5 prime UTR NM_194322.3:c.169G>T NP_919303.1:p.Glu57Ter nonsense NC_000002.12:g.26477725C>A NC_000002.11:g.26700593C>A NG_009937.1:g.85974G>T - Protein change
- E747*, E57*
- Other names
- NM_194248.2:c.2239G>T, p.(Glu747*)
- Canonical SPDI
- NC_000002.12:26477724:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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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LOC129933334 | - | - | - | GRCh38 | - | 38 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000056026.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2017 | RCV000211840.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2023 | RCV000318963.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 6, 2024 | RCV003905022.1 |
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
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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
(Aug 01, 2020)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 9
Affected status: yes
Allele origin:
germline
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King Laboratory, University of Washington
Accession: SCV001976367.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
OTOF c.2239G>T, p.E747* is homozygous in 2 children with profound pre-lingual hearing loss in a Palestinian family (Abu Rayyan 2020). It is absent from 1300 … (more)
OTOF c.2239G>T, p.E747* is homozygous in 2 children with profound pre-lingual hearing loss in a Palestinian family (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 1/249840 allele on gnomAD, as a heterozygote (less)
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Pathogenic
(May 04, 2017)
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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: SCV000199794.5
First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Glu747X variant in OTOF has been reported in the homozygous state in four individuals with hearing loss, including 1 individual with auditory neuropathy b … (more)
The p.Glu747X variant in OTOF has been reported in the homozygous state in four individuals with hearing loss, including 1 individual with auditory neuropathy b ased on the presence of otoacoustic emissions (Rodriguez-Ballesteros 2008 and LM M data). This variant has been identified in 1/33574 Latino chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs39 7515591); however, this frequency is low enough to be consistent with a recessiv e carrier frequency for hearing loss. This nonsense variant leads to a prematur e termination codon at position 747, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive auditory neuropathy spectrum disorder, based on the predicted impact to the protein, reported homozygosity in multiple affected individuals with consistent specific phenotypes, and the low frequency in the g eneral population. (less)
Number of individuals with the variant: 4
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Pathogenic
(Feb 09, 2022)
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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: SCV000329896.7
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; Not … (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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26188103, 18381613, 27766948, 29048421, 34194829, 32747562) (less)
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Pathogenic
(Sep 28, 2023)
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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: SCV004292093.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu747*) 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.Glu747*) 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 (rs397515591, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with OTOF-related conditions (PMID: 18381613, 27766948). ClinVar contains an entry for this variant (Variation ID: 65787). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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OTOF-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004727419.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The OTOF c.2239G>T variant is predicted to result in premature protein termination (p.Glu747*). This variant has been reported as causative for autosomal recessive nonsyndromic hearing … (more)
The OTOF c.2239G>T variant is predicted to result in premature protein termination (p.Glu747*). This variant has been reported as causative for autosomal recessive nonsyndromic hearing loss (Rodriguez-Ballesteros et al. 2008. PubMed ID: 18381613; Santarelli et al. 2015. PubMed ID: 26188103; Dallol et al. 2016. PubMed ID: 27766948; described as c.169G>T p.Glu57* in Almontashiri et al. 2018. PubMed ID: 29048421). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in OTOF are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806251.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 01, 2008)
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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: SCV000804277.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment on evidence:
In a 2-year-old child from a multiplex Libyan family with profound prelingual sensorineural hearing loss (DFNB9; 601071), Rodriguez-Ballesteros et al. (2008) detected homozygosity for a … (more)
In a 2-year-old child from a multiplex Libyan family with profound prelingual sensorineural hearing loss (DFNB9; 601071), Rodriguez-Ballesteros et al. (2008) detected homozygosity for a c.2239G-T transversion in exon 20 of the OTOF gene that resulted in a glu747-to-ter (E747X) amino acid substitution. The authors noted that the mutation affected both the long and the short isoforms of OTOF. In a Saudi Arabian brother and sister with severe to profound hearing impairment, Dallol et al. (2016) identified homozygosity for a c.2239G-T transversion (c.2239G-T, NM_194248) in the OTOF gene that resulted in an E747X amino acid substitution. The mutation was identified by targeted sequencing of 87 genes known to be involved in hearing impairment, and confirmed by Sanger sequencing. In 3 Saudi families (F-7, F-25, and F-27) with autosomal recessive prelingual sensorineural hearing loss, Almontashiri et al. (2018) identified homozygosity for the E747X mutation in the OTOF gene, which they designated c.169G-T (GLU57TER, E57X). The mutation was identified by targeted sequencing and confirmed by Sanger sequencing. Almontashiri et al. (2018) observed this variant in 1 of 251,632 alleles from non-Middle Eastern populations in the gnomAD database. (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: SCV000087086.2
First in ClinVar: Oct 02, 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 |
Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients. | Almontashiri NAM | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29048421 |
Utilization of amplicon-based targeted sequencing panel for the massively parallel sequencing of sporadic hearing impairment patients from Saudi Arabia. | Dallol A | BMC medical genetics | 2016 | PMID: 27766948 |
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 |
Text-mined citations for rs397515591 ...
HelpRecord last updated May 19, 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.