ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.2381G>A (p.Arg794His)
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.
Uncertain significance(2); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_194248.3(OTOF):c.2381G>A (p.Arg794His)
Variation ID: 21835 Accession: VCV000021835.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26477441 (GRCh38) [ NCBI UCSC ] 2: 26700309 (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 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194248.3:c.2381G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Arg794His missense NM_194323.3:c.140G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919304.1:p.Arg47His missense NM_001287489.2:c.2381G>A NP_001274418.1:p.Arg794His missense NM_004802.4:c.140G>A NP_004793.2:p.Arg47His missense NM_194322.3:c.311G>A NP_919303.1:p.Arg104His missense NC_000002.12:g.26477441C>T NC_000002.11:g.26700309C>T NG_009937.1:g.86258G>A Q9HC10:p.Arg794His - Protein change
- R794H, R104H, R47H
- Other names
- -
- Canonical SPDI
- NC_000002.12:26477440:C: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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0.00240 (T)
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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 0.00109
The Genome Aggregation Database (gnomAD) 0.00122
Trans-Omics for Precision Medicine (TOPMed) 0.00144
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00170
Exome Aggregation Consortium (ExAC) 0.00178
1000 Genomes Project 0.00240
1000 Genomes Project 30x 0.00250
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 | ||
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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
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. |
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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
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000021047.11 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2022 | RCV000041494.8 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000955909.22 |
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. |
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001135637.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Aug 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001476589.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Jul 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571056.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: OTOF c.2381G>A (p.Arg794His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: OTOF c.2381G>A (p.Arg794His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 220574 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2381G>A has been found in the heterozygous state (with no second OTOF variant reported) in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Schrauwen_2013). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 29, 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: SCV001102646.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Likely benign
(Aug 06, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065189.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
p.Arg794His in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (71/26210) of … (more)
p.Arg794His in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (71/26210) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356592). (less)
Number of individuals with the variant: 7
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001296880.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498533.13
First in ClinVar: Apr 08, 2022 Last updated: May 12, 2024 |
Comment:
OTOF: PP3, BS1:Supporting
Number of individuals with the variant: 3
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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: SCV000041701.2
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 |
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing. | Schrauwen I | American journal of medical genetics. Part A | 2013 | PMID: 23208854 |
Screening of OTOF mutations in Iran: a novel mutation and review. | Mahdieh N | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22906306 |
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 rs80356592 ...
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.