NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter) AND Rare genetic deafness

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 20, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000211838.14

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]

Observations:

Condition(s)

Name:: Rare genetic deafness
Identifiers:: MedGen: C5680250; Orphanet: 96210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000065196	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 20, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27177047, 14635104, 12114484, 16371502, 18381613, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065196

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 20, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	10	6	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular study of patients with auditory neuropathy.

Carvalho GM, Ramos PZ, Castilho AM, Guimarães AC, Sartorato EL.

Mol Med Rep. 2016 Jul;14(1):481-90. doi: 10.3892/mmr.2016.5226. Epub 2016 May 9.

PubMed [citation]

PMID:: 27177047

Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF).

Rodríguez-Ballesteros M, del Castillo FJ, Martín Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Terán J, Morales-Angulo C, Navas C, Trinidad G, Tapia MC, Moreno F, del Castillo I.

Hum Mutat. 2003 Dec;22(6):451-6.

PubMed [citation]

PMID:: 14635104

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065196.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Gln829X variant in OTOF has been previously reported in >30 individuals with hearing loss or auditory neuropathy, all of whom were homozygous or compound heterozygous for a second pathogenic OTOF variant, and segregated in >10 affected relatives (Migliosi 2002, Rodriguez-Ballesteros 2003, Rodriguez-Ballesteros 2008, Varga 2006). This variant has been identified in 0.06% (22/34228) of Latino chromosomes by gnomAD, and has been reported to be a founder variant in the Spanish population based on linkage data (Migliosi 2002; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 829, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOF gene is an established disease mechanism in autosomal recessive auditory neuropathy spectrum disorder. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive auditory neuropathy spectrum disorder. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		10	not provided	6	not provided

Last Updated: Nov 3, 2024

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