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NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter) AND Nonsyndromic genetic hearing loss

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 13, 2022
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002227998.10

Allele description [Variation Report for NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)]

NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)

Gene:
OTOF:otoferlin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p23.3
Genomic location:
Preferred name:
NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)
Other names:
NM_194248.3(OTOF):c.2485C>T
HGVS:
  • NC_000002.12:g.26477210G>A
  • NG_009937.1:g.86489C>T
  • NM_001287489.2:c.2485C>T
  • NM_004802.4:c.244C>T
  • NM_194248.3:c.2485C>TMANE SELECT
  • NM_194322.3:c.415C>T
  • NM_194323.3:c.244C>T
  • NP_001274418.1:p.Gln829Ter
  • NP_004793.2:p.Gln82Ter
  • NP_919224.1:p.Gln829Ter
  • NP_919224.1:p.Gln829Ter
  • NP_919224.1:p.Gln829Ter
  • NP_919303.1:p.Gln139Ter
  • NP_919304.1:p.Gln82Ter
  • NC_000002.11:g.26700078G>A
  • NM_194248.1:c.2485C>T
  • NM_194248.2:c.2485C>T
  • NM_194248.3:c.2485C>T
  • c.2485C>T
  • p.Gln829X
Protein change:
Q139*; GLN829TER
Links:
OMIM: 603681.0004; dbSNP: rs80356593
NCBI 1000 Genomes Browser:
rs80356593
Molecular consequence:
  • NM_001287489.2:c.2485C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_004802.4:c.244C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_194248.3:c.2485C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_194322.3:c.415C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_194323.3:c.244C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Nonsyndromic genetic hearing loss
Synonyms:
Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:
MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002512132ClinGen Hearing Loss Variant Curation Expert Panel
reviewed by expert panel

(clingen hl acmg specifications otof myo15a v1)		Pathogenic
(May 13, 2022) 		germlinecuration

Citation Link,

SCV004222718Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Nov 15, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

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, Reynoso R, Olarte M, Villamar M, Morera C, Santarelli R, Arslan E, Medá C, Curet C, Völter C, Sainz-Quevedo M, Castorina P, Ambrosetti U, Berrettini S, Frei K, Tedín S, Smith J, Cruz Tapia M, Cavallé L, Gelvez N, Primignani P, Gómez-Rosas E, et al.

Hum Mutat. 2008 Jun;29(6):823-31. doi: 10.1002/humu.20708.

PubMed [citation]
PMID:
18381613

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV002512132.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for Latino chromosomes in gnomAD v2.1.1, which meets the cutoff to apply BS1_Supporting. However, this variant has been established as a founder variant in the Spanish population and is thought to be causative in 3% of cases of deafness in the Spanish population (BS1_Supporting not applicable; PMID: 27177047). The p.Gln829Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 21/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID: 30192042). The p.Gln829Ter variant has been identified in >50 patients with non-syndromic hearing loss (PM3_VeryStrong; PMIDs: 18381613, 17036997, 16371502, 14635104, 12114484). It has repeatedly been reported to segregate with hearing loss (PP1_Strong; PMIDs: 12114484, 14635104,16371502, 18381613). In addition to hearing loss, at least 24 patients reported to have the p.Gln829Ter variant presented with features of auditory neuropathy spectrum disorder, which is highly specific to OTOF and autosomal recessive hearing loss (PP4; PMIDs:18381613, 17036997, 14635104). In summary, the p.Gln829Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PP1_Strong, PM3_VeryStrong, PP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004222718.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: OTOF c.2485C>T (p.Gln829X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00017 in 243966 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00017 vs 0.0011), allowing no conclusion about variant significance. c.2485C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Rodriguez-Ballesteros_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18381613). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 26, 2024