NM_194248.3(OTOF):c.5098G>C (p.Glu1700Gln) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Mar 20, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV000413616.12

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000490937	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 20, 2025)	germline	clinical testing	Citation Link,
SCV001560624	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20224275, 25326637, 31827501, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490937

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 20, 2025)

germline

clinical testing

Citation Link,

SCV001560624

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 12, 2022)

germline

clinical testing

PubMed (4)
[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
not provided	germline	yes	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

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000490937.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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: 34416374, 31827501, 20224275, 24746455, 20301429, 31180159, 25326637, 28766844, 32508568, 30368385, 31980526, 32555439, 33256196, 34325055, 35114279, 34943631, 34335733, 35106950, 36837553, 34536124, 34424407, 34692690, 30311386, 35884828)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001560624.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1700 of the OTOF protein (p.Glu1700Gln). This variant is present in population databases (rs199766465, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with OTOF-related conditions (PMID: 20224275, 25326637, 31827501). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48253). 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) performed at Invitae indicates that this missense variant is expected to disrupt OTOF protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Jun 22, 2025

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