ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.4748G>A (p.Arg1583His)
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.4748G>A (p.Arg1583His)
Variation ID: 2429109 Accession: VCV002429109.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 26465723 (GRCh38) [ NCBI UCSC ] 2: 26688591 (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 Feb 13, 2023 Feb 14, 2024 Aug 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194248.3:c.4748G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Arg1583His missense NM_194323.3:c.2447G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919304.1:p.Arg816His missense NM_001287489.2:c.4748G>A NP_001274418.1:p.Arg1583His missense NM_004802.4:c.2447G>A NP_004793.2:p.Arg816His missense NM_194248.2:c.4748G>A NM_194322.3:c.2678G>A NP_919303.1:p.Arg893His missense NC_000002.12:g.26465723C>T NC_000002.11:g.26688591C>T NG_009937.1:g.97976G>A - Protein change
- R1583H, R816H, R893H
- Other names
- NM_194323.3:c.2447G>A
- Canonical SPDI
- NC_000002.12:26465722: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 |
1931 | 2066 |
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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Likely pathogenic (1) |
reviewed by expert panel
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Aug 3, 2022 | RCV003123349.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV003228140.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV003331454.1 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Aug 03, 2022)
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reviewed by expert panel
Method: curation
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Autosomal recessive nonsyndromic hearing loss 9
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV003799178.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
The c.4748G>A variant in OTOF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1583. The highest population minor … (more)
The c.4748G>A variant in OTOF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1583. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16254 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). Another missense variant c.4747C>T (p.R1583C) (PMID:26818607, 31589614, 32747562, 33724713, 34426522, ClinVar Variation ID:402270) in the same codon has been classified as pathogenic/likely pathogenic for autosomal recessive nonsyndromic hearing loss in ClinVar (PM5). At least one patient with this variant and compound heterozygous for the c.2215-1G>C variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for ANSD (PP4, PMID:24001616). This variant has been detected in at least 1 individual with ANSD, who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant were confirmed in trans by family testing (c.2215-1G>C, 1 PM3 point, PMID:24001616). Additional compound heterozygous cases with variants c.5816G>A (p.R1939Q), c.3515G>A (p.R1172Q), and c.2523+1G>T (PMIDs: 24053799, 31095577, 31827501 respectively) were also seen, but excluded from scoring due to less scorable evidence. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PM5, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022). (less)
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Likely pathogenic
(May 11, 2023)
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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: SCV003924701.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
Observed in other unrelated patients with hearing loss in published literature (Iwasa et al., 2013; Iwasa et al., 2019); Not observed at significant frequency in … (more)
Observed in other unrelated patients with hearing loss in published literature (Iwasa et al., 2013; Iwasa et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24053799, 31095577, 31827501, 24001616) (less)
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Likely pathogenic
(Aug 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: SCV004039107.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: OTOF c.4748G>A (p.Arg1583His) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five … (more)
Variant summary: OTOF c.4748G>A (p.Arg1583His) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes (gnomAD). c.4748G>A has been reported in the literature in at least four compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Iwasa_2013, Zhang_2013, Qiu_2019, Iwasa_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24001616, 24053799, 31095577, 31827501). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Apr 13, 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: SCV004292076.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1583 amino acid residue in OTOF. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1583 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26818607, 32747562, 33724713, 34424407). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. ClinVar contains an entry for this variant (Variation ID: 2429109). This missense change has been observed in individual(s) with auditory neuropathy and/or clinical features of OTOF-related conditions (PMID: 24001616, 24053799, 31095577, 31827501). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs139416718, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1583 of the OTOF protein (p.Arg1583His). (less)
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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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The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study. | Thorpe RK | Human genetics | 2022 | PMID: 34424407 |
Targeted next-generation sequencing of deaf patients from Southwestern China. | Li Y | Molecular genetics & genomic medicine | 2021 | PMID: 33724713 |
Genomic analysis of inherited hearing loss in the Palestinian population. | Abu Rayyan A | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 32747562 |
Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families. | Qiu Y | Neural plasticity | 2019 | PMID: 31827501 |
OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients. | Iwasa YI | PloS one | 2019 | PMID: 31095577 |
High frequency of OTOF mutations in Chinese infants with congenital auditory neuropathy spectrum disorder. | Zhang QJ | Clinical genetics | 2016 | PMID: 26818607 |
OTOF mutation screening in Japanese severe to profound recessive hearing loss patients. | Iwasa Y | BMC medical genetics | 2013 | PMID: 24053799 |
Identification of novel OTOF compound heterozygous mutations by targeted next-generation sequencing in a Chinese patient with auditory neuropathy spectrum disorder. | Zhang LP | International journal of pediatric otorhinolaryngology | 2013 | PMID: 24001616 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/42cb25c9-af9e-4a41-8e82-25e04ca787fc | - | - | - | - |
Text-mined citations for this variant ...
HelpRecord last updated Feb 20, 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.