The p.Arg1792His variant in OTOF has been previously reported by our laboratory in 3 individuals with hearing loss, including two homozygotes and one with audit ory neuropathy spectrum disorder (ANSD) who was compound heterozygous for a seco nd pathogenic variant in OTOF. This variant has been reported in 1/11258 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs111033349); however, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant is likely pathogenic for autosomal recessive hearing loss.
ClinVar Genomic variation as it relates to human health
NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)
Variation ID: 48259 Accession: VCV000048259.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p23.3 2: 26461854 (GRCh38) [ NCBI UCSC ] 2: 26684722 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 31, 2015 Sep 29, 2024 Sep 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_194248.3:c.5375G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919224.1:p.Arg1792His missense NM_194323.3:c.3074G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919304.1:p.Arg1025His missense NM_001287489.2:c.5375G>A NP_001274418.1:p.Arg1792His missense NM_004802.4:c.3074G>A NP_004793.2:p.Arg1025His missense NM_194322.3:c.3305G>A NP_919303.1:p.Arg1102His missense NC_000002.12:g.26461854C>T NC_000002.11:g.26684722C>T NG_009937.1:g.101845G>A - Protein change
- R1792H, R1025H, R1102H
- Other names
- -
- Canonical SPDI
- NC_000002.12:26461853:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| OTOF | - | - |
GRCh38 GRCh37 |
1987 | 2126 | |
Conditions - Germline
| Condition
Help
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2016 | RCV000041571.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 9, 2024 | RCV000171287.7 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Mar 17, 2024 | RCV000656336.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Dec 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065266.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Arg1792His variant in OTOF has been previously reported by our laboratory in 3 individuals with hearing loss, including two homozygotes and one with audit … (more)
The p.Arg1792His variant in OTOF has been previously reported by our laboratory in 3 individuals with hearing loss, including two homozygotes and one with audit ory neuropathy spectrum disorder (ANSD) who was compound heterozygous for a seco nd pathogenic variant in OTOF. This variant has been reported in 1/11258 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs111033349); however, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant is likely pathogenic for autosomal recessive hearing loss. (less)
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004292075.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). This variant is present in population databases (rs111033349, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive OTOF-related conditions (PMID: 29048421, 31095577, 34424407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48259). 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. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31095577, 34416374, 34536124; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive nonsyndromic hearing loss 9
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804932.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Sep 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002526636.3
First in ClinVar: Jun 24, 2022 Last updated: Sep 29, 2024 |
Comment:
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; … (more)
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: 27124789, 29048421, 34424407, 38378725, 31095577) (less)
|
|
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Pathogenic
(Aug 31, 2018)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000804276.1
First in ClinVar: Jun 04, 2018 Last updated: Jun 04, 2018 |
Comment on evidence:
In affected members from 4 (F-18, F-22, F-31, and F-32) of 33 Saudi families with autosomal recessive prelingual sensorineural hearing loss (DFNB9; 601071), Almontashiri et … (more)
In affected members from 4 (F-18, F-22, F-31, and F-32) of 33 Saudi families with autosomal recessive prelingual sensorineural hearing loss (DFNB9; 601071), Almontashiri et al. (2018) identified homozygosity for a c.5375G-A transition in the OTOF gene that resulted in an arg1792-to-his (R1792H) amino acid substitution. Almontashiri et al. (2018) observed this variant in 1 of 252,426 alleles from non-Middle Eastern populations in the gnomAD database. (less)
|
|
|
Likely pathogenic
(Feb 13, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 9
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV000778299.1
First in ClinVar: Jun 04, 2018 Last updated: Jun 04, 2018 |
|
|
|
Likely pathogenic
(-)
|
Flagged submission
flagged submission
Method: research
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000221484 appears to be redundant with SCV004804932.
(less)
Notes: SCV000221484 appears to
(...more)
Source: NCBI
|
Not provided
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV000221484.1
First in ClinVar: May 31, 2015 Last updated: May 31, 2015 |
Indication for testing: Audiologic phenotype and hearing loss
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). This variant is present in population databases (rs111033349, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive OTOF-related conditions (PMID: 29048421, 31095577, 34424407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48259). 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. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31095577, 34416374, 34536124; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 27124789, 29048421, 34424407, 38378725, 31095577)
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. |
Comment:
The p.Arg1792His variant in OTOF has been previously reported by our laboratory in 3 individuals with hearing loss, including two homozygotes and one with audit ory neuropathy spectrum disorder (ANSD) who was compound heterozygous for a seco nd pathogenic variant in OTOF. This variant has been reported in 1/11258 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs111033349); however, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant is likely pathogenic for autosomal recessive hearing loss.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). This variant is present in population databases (rs111033349, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive OTOF-related conditions (PMID: 29048421, 31095577, 34424407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48259). 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. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31095577, 34416374, 34536124; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 27124789, 29048421, 34424407, 38378725, 31095577)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan. | Iwasa YI | Human genetics | 2022 | PMID: 34536124 |
| The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study. | Thorpe RK | Human genetics | 2022 | PMID: 34424407 |
| Family trio-based sequencing in 404 sporadic bilateral hearing loss patients discovers recessive and De novo genetic variants in multiple ways. | Guan J | European journal of medical genetics | 2021 | PMID: 34416374 |
| OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients. | Iwasa YI | PloS one | 2019 | PMID: 31095577 |
| 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 |
Text-mined citations for rs111033349 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.