NM_194248.3(OTOF):c.5375G>A (p.Arg1792His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000171287.10

Allele description [Variation Report for NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)]

NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)

Gene:

OTOF:otoferlin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)

HGVS:

NC_000002.12:g.26461854C>T
NG_009937.1:g.101845G>A
NM_001287489.2:c.5375G>A
NM_004802.4:c.3074G>A
NM_194248.3:c.5375G>AMANE SELECT
NM_194322.3:c.3305G>A
NM_194323.3:c.3074G>A
NP_001274418.1:p.Arg1792His
NP_004793.2:p.Arg1025His
NP_919224.1:p.Arg1792His
NP_919303.1:p.Arg1102His
NP_919304.1:p.Arg1025His
NC_000002.11:g.26684722C>T
NM_001287489.1:c.5375G>A
NM_004802.3:c.3074G>A
NM_194248.2:c.5375G>A
NM_194248.3:c.5375G>A
c.5375G>A

Protein change:

R1025H; ARG1792HIS

Links:

OMIM: 603681.0015; dbSNP: rs111033349

Molecular consequence:

NM_001287489.2:c.5375G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004802.4:c.3074G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_194248.3:c.5375G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_194322.3:c.3305G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_194323.3:c.3074G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002526636	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 9, 2024)	germline	clinical testing	Citation Link,
SCV004292075	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29048421, 34424407, 31095577, 34416374, 34536124, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002526636

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 9, 2024)

germline

clinical testing

Citation Link,

SCV004292075

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients.

Almontashiri NAM, Alswaid A, Oza A, Al-Mazrou KA, Elrehim O, Tayoun AA, Rehm HL, Amr SS.

Genet Med. 2018 Apr;20(5):536-544. doi: 10.1038/gim.2017.143. Epub 2017 Oct 19.

PubMed [citation]

PMID:: 29048421
PMCID:: PMC5929117

See all PubMed Citations (7)

Details of each submission

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV000221484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	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 GeneDx, SCV002526636.3

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); 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: 27124789, 29048421, 34424407, 38378725, 31095577)

#	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, SCV004292075.3

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). This variant is present in population databases (rs111033349, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive OTOF-related conditions (PMID: 29048421, 31095577, 34424407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48259). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31095577, 34416374, 34536124; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221484	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	flagged submission Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000221484 appears to be redundant with SCV004804932. (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000221484

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

flagged submission

Reason: This record appears to be redundant with a more recent record from the same submitter.

Notes: SCV000221484 appears to be redundant with SCV004804932.

(ACMG Guidelines, 2015)

Likely pathogenic

germline

research

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

Last Updated: Apr 12, 2026

ClinVar

Relating variation to medicine