NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 10, 2024
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:: RCV000757590.17

Allele description [Variation Report for NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe)]

NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe)

Gene:

OTOF:otoferlin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe)

HGVS:

NC_000002.12:g.26461897C>A
NG_009937.1:g.101802G>T
NM_001287489.2:c.5332G>T
NM_004802.4:c.3031G>T
NM_194248.3:c.5332G>TMANE SELECT
NM_194322.3:c.3262G>T
NM_194323.3:c.3031G>T
NP_001274418.1:p.Val1778Phe
NP_004793.2:p.Val1011Phe
NP_919224.1:p.Val1778Phe
NP_919303.1:p.Val1088Phe
NP_919304.1:p.Val1011Phe
NC_000002.11:g.26684765C>A
NM_194248.2:c.5332G>T
NM_194248.3:c.5332G>T
c.5332G>T

Protein change:

V1011F

Links:

dbSNP: rs111033330

NCBI 1000 Genomes Browser:

rs111033330

Molecular consequence:

NM_001287489.2:c.5332G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004802.4:c.3031G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_194248.3:c.5332G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_194322.3:c.3262G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_194323.3:c.3031G>T - 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
SCV000885879	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jul 31, 2017)	germline	clinical testing	Citation Link,
SCV002279968	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27621663, 28492532
SCV002762002	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 8, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000885879

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Jul 31, 2017)

germline

clinical testing

Citation Link,

SCV002279968

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 10, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002762002

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 8, 2022)

germline

clinical testing

Citation Link

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a novel pathogenic OTOF variant causative of nonsyndromic hearing loss with high frequency in the Ashkenazi Jewish population.

Fedick AM, Jalas C, Swaroop A, Smouha EE, Webb BD.

Appl Clin Genet. 2016;9:141-6. doi: 10.2147/TACG.S113828.

PubMed [citation]

PMID:: 27621663
PMCID:: PMC5012844

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885879.1

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

Description

The p.Val1778Phe variant (rs111033330) has been previously reported in association with auditory neuropathy in an Ashkenazi Jewish family (Fedick 2016). Fedick et al reported 4 siblings homozygous for the p.Val1778Phe variant with highly variable degrees of hearing loss (mild to moderately -severe) and auditory brainstem response testing consistent with auditory neuropathy/dys-synchrony. This variant has been reported to ClinVar (Variation ID: 48258) and according to information provided by Fedick et al the entry from Partners HealthCare represents a 2nd Jewish family with the p.Val1778Phe variant in trans with a known pathogenic variant, but that information is not available on ClinVar. The p.Val1778Phe variant is predicted to be more frequent in Ashkenazi Jewish individuals than in other populations with an estimated frequency of 0.4 - 1.27 percent (gnomAD, and Fedick 2016). Altogether, there is not enough evidence to classify the p.Val1778Phe variant with certainty.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002279968.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1778 of the OTOF protein (p.Val1778Phe). This variant is present in population databases (rs111033330, gnomAD 0.5%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 27621663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48258). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

From GeneDx, SCV002762002.1

#	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: 27621663)

#	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

Last Updated: Sep 29, 2024

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