2-26479356-G-A

Position:

chr2-26479356-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM3_StrongPP1_StrongPVS1PP4

This summary comes from the ClinGen Evidence Repository: The c.2122C>T (p.Arg708Ter) variant in OTOF has been reported in reported in at least 11 individuals with autosomal recessive nonsyndromic hearing loss, including 2 probands who were compound heterozygous for a second nonsense variant in OTOF (confirmed in trans in one of these cases) and 9 homozygous probands, and segregated with disease in at least 17 affected family members from 7 families (PM3_Strong, PP1_Strong; PMID:14635104, 18381613, 26029705, 29434063, 19250381; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). It has also been identified in 0.0162% (4/24,692) of African/African-American alleles in gnomAD v2 (gnomad.broadinstitute.org). The p.Arg708Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 18/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID:30192042). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). In summary, the p.Arg708Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_Strong, PP1_Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA342562/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

OTOF
NM_194248.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 2.22

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 17 ACMG points.

PVS1

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

PM3

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

PP1

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.2122C>T	p.Arg708*	stop_gained	18/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 linkuse as main transcript	c.2122C>T	p.Arg708*	stop_gained	18/46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2122C>T	p.Arg708*	stop_gained	18/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.2122C>T	p.Arg708*	stop_gained	18/46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248752

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1460478

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The homozygous variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000021831 / PMID: 14635104). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research	Feb 15, 2020	Candidate homozygous variant segregating well with the disease phenotype -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 30, 2020	This sequence change creates a premature termination codon at position 708 in exon 18 (of 47) of OTOF (p.(Arg708*)). It is expected to result in nonsense mediated decay, where loss of function is a well-established mechanism of disease for this gene (ClinGen). The variant is present in a large population cohort at a frequency of 0.002% (rs80356590, 7/280,138 alleles, 0 homozygotes in gnomAD v2.1.1). The variant has been identified in both the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with either prelingual nonsyndromic hearing loss or auditory neuropathy, and segregates with disease in multiple families (PMID: 14635104, 19250381). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PP1_Strong, PM2_Supporting. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2023	This sequence change creates a premature translational stop signal (p.Arg708*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs80356590, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 34113375). ClinVar contains an entry for this variant (Variation ID: 21831). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301429, 16097006, 26186295, 25525159, 14635104, 19250381, 26029705, 29434063, 22906306, 30303587, 34113375, 31345219, 36147510) -

OTOF-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The OTOF c.2122C>T variant is predicted to result in premature protein termination (p.Arg708*). This variant was reported in two individuals with deafness, non-syndromic (Rodriguez-Ballesteros et al 2003. PubMed ID: 14635104; Fareed et al. 2021. PubMed ID: 34113375). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Nonsense variants in OTOF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 23, 2021

The c.2122C>T (p.Arg708Ter) variant in OTOF has been reported in reported in at least 11 individuals with autosomal recessive nonsyndromic hearing loss, including 2 probands who were compound heterozygous for a second nonsense variant in OTOF (confirmed in trans in one of these cases) and 9 homozygous probands, and segregated with disease in at least 17 affected family members from 7 families (PM3_Strong, PP1_Strong; PMID: 14635104, 18381613, 26029705, 29434063, 19250381; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). It has also been identified in 0.0162% (4/24,692) of African/African-American alleles in gnomAD v2 (gnomad.broadinstitute.org). The p.Arg708Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 18/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID: 30192042). At least one patient with this variant displayed features of auditory neuropathy spectrum disorder, which is highly specific for OTOF (PP4; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6). In summary, the p.Arg708Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_Strong, PP1_Strong, PP4. -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2012

The Arg708X variant in OTOF has been reported in 3 individuals with hearing loss and segregated with disease in six affected family members (Choi 2009, Rodrigue z-Ballesteros 2003). This nonsense variant leads to a premature termination codo n at position 708, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http ://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.79

Vest4

0.82

GERP RS

2.6

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