NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln) AND Rare genetic deafness

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 10, 2024
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:: RCV004017335.1

Allele description [Variation Report for NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln)]

NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln)

Genes:

LOC112840921:BRD4-independent group 4 enhancer GRCh37_chr2:26685720-26686919 [Gene]
OTOF:otoferlin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln)

Other names:

DFNB9: otoferlin; NM_194248.2(OTOF):c.5098G>C

HGVS:

NC_000002.12:g.26463969C>G
NG_009937.1:g.99730G>C
NG_060956.1:g.449C>G
NM_001287489.2:c.5098G>C
NM_004802.4:c.2797G>C
NM_194248.3:c.5098G>CMANE SELECT
NM_194322.3:c.3028G>C
NM_194323.3:c.2797G>C
NP_001274418.1:p.Glu1700Gln
NP_004793.2:p.Glu933Gln
NP_919224.1:p.Glu1700Gln
NP_919303.1:p.Glu1010Gln
NP_919304.1:p.Glu933Gln
NC_000002.11:g.26686837C>G
NM_194248.1:c.5098G>C
NM_194248.2:c.5098G>C
NM_194248.3:c.5098G>C
c.5098G>C

Protein change:

E1010Q

Links:

dbSNP: rs199766465

NCBI 1000 Genomes Browser:

rs199766465

Molecular consequence:

NM_001287489.2:c.5098G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004802.4:c.2797G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_194248.3:c.5098G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_194322.3:c.3028G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_194323.3:c.2797G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein [Variation Ontology: 0002]

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
SCV000065260	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 10, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20224275, 30368385, 28766844, 34692690, 25326637, 31827501, 34416374, 35106950, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065260

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 10, 2024)

germline

clinical testing

PubMed (9)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the OTOF gene in Taiwanese patients with auditory neuropathy.

Chiu YH, Wu CC, Lu YC, Chen PJ, Lee WY, Liu AY, Hsu CJ.

Audiol Neurootol. 2010;15(6):364-74. doi: 10.1159/000293992. Epub 2010 Mar 11.

PubMed [citation]

PMID:: 20224275

Targeted next generation sequencing reveals OTOF mutations in auditory neuropathy spectrum disorder.

Chen K, Liu M, Wu X, Zong L, Jiang H.

Int J Pediatr Otorhinolaryngol. 2018 Dec;115:19-23. doi: 10.1016/j.ijporl.2018.09.008. Epub 2018 Sep 14. Review.

PubMed [citation]

PMID:: 30368385

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065260.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Glu1700Gln variant in OTOF has been reported in >15 compound heterozygous or homozygous individuals with auditory neuropathy and/or hearing loss and segregated with disease in at least 3 affected individuals from 2 families. However some of these individuals had pathogenic variants in other genes which explained their phenotype (Chiu 2010 PMID: 20224275, Lee 2014 PMID: 25326637, Chen 2018 PMID: 30368385, Wu 2018 PMID: 28766844, Qiu 2019 PMID: 31827501, Guan 2021 PMID: 34416374, Zhu 2021 PMID: 34692690, Liu 2022 PMID: 35106950, LMM data). It has also been identified in 0.33% (152/44874) of East Asian chromosomes by gnomAD including 1 homozygote (http://gnomad.broadinstitute.org, v.4.0.0). This variant was classified as Uncertain Significance on Jun 23, 2021 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 48253). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain due to conflicting information. ACMG/AMP Criteria applied: BS1, PM3_Strong, PP1_Strong, PP3.

#	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		not provided	not provided	not provided	not provided

Last Updated: May 25, 2025

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