2-26463969-C-G

Position:

chr2-26463969-C-G

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP4PM3PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.5098G>C (p.Glu1700Gln) variant in OTOF is a missense variant predicted to cause a substitution of glutamic acid by glutamine at amino acid 1700. The filtering allele frequency (the lower threshold of the 95% CI of 152/44874) of the c.5098G>C (p.Glu1700Gln) is 0.2948% for East Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency the East Asian population, given it is reported as a founder mutation in the Taiwanese population (PMID:20224275). Therefore, the BS1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.85 which is above the threshold of ≥ 0.7 (PP3). This variant has been detected in at least 18 individuals with autosomal recessive nonsyndromic hearing loss. Eight individuals were homozygous for the variant (PMIDs: 20224275, 35106950). Six individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Glu841Lys, c.4961-1G>A, p.Arg1344*, p.Arg500*; PMID:28766844). Four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and confirmed in trans by parental testing (p.Pro1628Thr; PMID:34692690) (PM3_VeryStrong). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; PMID:28766844). The variant has been reported to segregate with hearing loss in multiple affected family members from two families (PP1_Strong; PMIDs: 20224275, 34692690). In summary, this variant meets the criteria to be classified as pathogenic for nonsyndromic genetic hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM3_VeryStrong, PP4, PP1_Strong; Version 2; 5/15/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA345132/MONDO:0019497/023

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

OTOF
ENST00000272371.7 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6U:4O:1

Conservation

PhyloP100: 7.87

Variant links:

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5098G>C	p.Glu1700Gln	missense_variant	40/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.2797G>C	p.Glu933Gln	missense_variant	23/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.5098G>C	p.Glu1700Gln	missense_variant	40/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.2797G>C	p.Glu933Gln	missense_variant	23/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00636

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000512

AC:

128

AN:

249992

Hom.:

AF XY:

0.000421

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00691

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000924

AC:

135

AN:

1461470

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000210

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00618

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000635

Hom.:

Bravo

AF:

0.000246

ExAC

AF:

0.000535

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:3Uncertain:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	Nanfang Hospital, Southern Medical University	Aug 16, 2021	The c.5098G>C (p.Glu1700Gln) variant was observed with the other variant, c.4882C>A (p.Pro1628Thr), in compound heterozygosity in a Chinese family with temperature-sensitive auditory neuropathy, segregated with the disease in 4 patients in the present study, and was absent in 200 normal-hearing controls matched for Chinese ethnicity. It has also been reported in several other patients (Chiu et al., 2010; Chen et al., 2018; Qiu et al., 2019; Wu et al., 2019). Additionally, in vitro bioinformatics analysis indicate that the c.5098G>C (p.Glu1700Gln) variant perturbs an amino acid side chain and has lost the hydrogen bonds between p.Glu1700 and p.Leu1704. In summary, the c.5098G>C (p.Glu1700Gln) variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional prediction. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 05, 2018	Across a selection of availabe literature, the OTOF c.5098G>C (p.Glu1700Gln) variant has been reported in at least three studies and is found in at least 21 probands including at least eight in a homozygous state, eight in a compound heterozygous state, and three in a heterozygous state (Chiu et al. 2010; Wu et al. 2011; Wu et al. 2018). The p.Glu1700Gln variant is described as founder variant that has been seen in up to 20% of Taiwanese auditory neuropathy/auditory dys-synchrony probands (Jin et al. 2014). The p.Glu1700Gln variant was absent from 100 ethnically-matched control individuals and is reported at a frequency of 0.007430 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Glu1700Gln variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PP3_Moderate+PM3+PP1 -

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2022	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. -

Auditory neuropathy spectrum disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University

Jun 11, 2020

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 28, 2024

The c.5098G>C (p.Glu1700Gln) variant in OTOF is a missense variant predicted to cause a substitution of glutamic acid by glutamine at amino acid 1700. The filtering allele frequency (the lower threshold of the 95% CI of 152/44874) of the c.5098G>C (p.Glu1700Gln) is 0.2948% for East Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency the East Asian population, given it is reported as a founder mutation in the Taiwanese population (PMID: 20224275). Therefore, the BS1 code will not contribute to the overall classification. The computational predictor REVEL gives a score of 0.85 which is above the threshold of ≥ 0.7 (PP3). This variant has been detected in at least 18 individuals with autosomal recessive nonsyndromic hearing loss. Eight individuals were homozygous for the variant (PMIDs: 20224275, 35106950). Six individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Glu841Lys, c.4961-1G>A, p.Arg1344*, p.Arg500*; PMID: 28766844). Four individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and confirmed in trans by parental testing (p.Pro1628Thr; PMID: 34692690) (PM3_VeryStrong). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; PMID: 28766844). The variant has been reported to segregate with hearing loss in multiple affected family members from two families (PP1_Strong; PMIDs: 20224275, 34692690). In summary, this variant meets the criteria to be classified as pathogenic for nonsyndromic genetic hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM3_VeryStrong, PP4, PP1_Strong; Version 2; 5/15/24). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 09, 2022

Variant summary: OTOF c.5098G>C (p.Glu1700Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 249992 control chromosomes, predominantly at a frequency of 0.0069 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.5098G>C has been reported in the literature as a frequent founder variant in the Taiwanese population (example, Chiu_2010), and as homozygous and compound heterozygous genotypes in individuals of East Asian ethnicity (EAS) from many simplex families affected with auditory neuropathy spectrum disorder (ANSD) (example, Chiu_2010, Lee_2014, Chen_2018, Qiu_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Pathogenic, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Rare genetic deafness

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;.;T;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.013

T;T;T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.1

.;.;.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.9

D;D;.;D;D;.

REVEL

Pathogenic

0.85

Sift

Benign

0.11

T;T;.;T;T;.

Sift4G

Benign

0.064

T;T;.;T;T;.

Polyphen

0.92

P;D;.;D;.;D

Vest4

0.84

MVP

0.95

MPC

0.51

ClinPred

0.21

GERP RS

4.4

Varity_R

0.44

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over