VCV000432017.36 - ClinVar

NM_001378609.3(OTOGL):c.5449C>T (p.Arg1817Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 7 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001378609.3(OTOGL):c.5449C>T (p.Arg1817Ter)

Variation ID: 432017 Accession: VCV000432017.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q21.31 12: 80353366 (GRCh38) [ NCBI UCSC ] 12: 80747146 (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	Aug 20, 2017	Apr 20, 2025	Jun 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378609.3:c.5449C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365538.2:p.Arg1817Ter	nonsense
NM_001368062.3:c.5314C>T	NP_001354991.2:p.Arg1772Ter	nonsense
NM_001378610.3:c.5449C>T	NP_001365539.2:p.Arg1817Ter	nonsense
NM_173591.7:c.5449C>T	NP_775862.4:p.Arg1817Ter	nonsense
NC_000012.12:g.80353366C>T
NC_000012.11:g.80747146C>T
NG_033008.1:g.148914C>T

... more HGVS ... less HGVS

Protein change

R1808*, R1772*, R1817*

Other names

Canonical SPDI

NC_000012.12:80353365:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00003

Exome Aggregation Consortium (ExAC) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA6701718 dbSNP: rs768620276 VarSome

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
Gene	OMIM	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.
OTOGL		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1041	1062

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.
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 5, 2024	RCV000497321.32
Autosomal recessive nonsyndromic hearing loss 84B	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 22, 2021	RCV002289684.5

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.
Pathogenic (Aug 25, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 84B Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805687.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jun 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589683.4 First in ClinVar: Aug 20, 2017 Last updated: Jul 23, 2024	Comment: Identified with a second OTOGL variant (phase unknown) in patients with bilateral childhood-onset sensorineural hearing loss referred for genetic testing at GeneDx and in published … (more) Identified with a second OTOGL variant (phase unknown) in patients with bilateral childhood-onset sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 35580552); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352160, 35580552) (less)
Pathogenic (Feb 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003290828.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 23122586 Comment: This sequence change creates a premature translational stop signal (p.Arg1808) in the OTOGL gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg1808) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 432017). 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)
Pathogenic (Dec 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 84B Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580419.2 First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025 Comment: ACMG criteria applied: PVS1, PS4_SUP, PM2_SUP, PM3_SUP	Number of individuals with the variant: 2 Sex: female
Likely pathogenic (Dec 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001747658.23 First in ClinVar: Jul 10, 2021 Last updated: Apr 20, 2025	Number of individuals with the variant: 2
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952780.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974850.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

Comment:

Identified with a second OTOGL variant (phase unknown) in patients with bilateral childhood-onset sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 35580552); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23352160, 35580552)

Comment:

This sequence change creates a premature translational stop signal (p.Arg1808*) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 432017). 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss.	Yariz KO	American journal of human genetics	2012	PMID: 23122586

Text-mined citations for rs768620276 ...

These 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 Apr 20, 2025

ClinVar Genomic variation as it relates to human health

NM_001378609.3(OTOGL):c.5449C>T (p.Arg1817Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs768620276 ...