rs80356590

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PP1_Strong; PMID:14635104, 18381613, 26029705, 29434063, 19250381; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6).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neuropathy spectrum disorder, which is highly specific for OTOF (PP4; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6).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

2
4
1

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]

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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
OTOFNM_194248.3 linkuse as main transcriptc.2122C>T p.Arg708* stop_gained 18/47 ENST00000272371.7 NP_919224.1 Q9HC10-1
OTOFNM_001287489.2 linkuse as main transcriptc.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
OTOFENST00000272371.7 linkuse as main transcriptc.2122C>T p.Arg708* stop_gained 18/471 NM_194248.3 ENSP00000272371.2 Q9HC10-1
OTOFENST00000403946.7 linkuse as main transcriptc.2122C>T p.Arg708* stop_gained 18/465 ENSP00000385255.3 Q9HC10-5

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152212
Hom.:
0
Cov.:
33
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:
9
AN:
248752
Hom.:
0
AF XY:
0.0000444
AC XY:
6
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:
56
AN:
1460478
Hom.:
0
Cov.:
34
AF XY:
0.0000372
AC XY:
27
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:
7
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
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:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000827
AC:
1
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 submitterclinical testing3billion-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 providedresearchIndian Institute of Integrative Medicine, Council of Scientific and Industrial ResearchFeb 15, 2020Candidate homozygous variant segregating well with the disease phenotype -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalNov 30, 2020This 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 providedliterature onlyGeneReviews-- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 11, 2023This 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 submitterclinical testingGeneDxMar 22, 2023Nonsense 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 providedclinical testingPreventionGenetics, part of Exact SciencesFeb 20, 2024The 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 panelcurationClinGen Hearing Loss Variant Curation Expert PanelMar 23, 2021The 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 providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 26, 2012The 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
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
44
DANN
Uncertain
1.0
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.79
D
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.

Other links and lift over

dbSNP: rs80356590; hg19: chr2-26702224; COSMIC: COSV55505900; COSMIC: COSV55505900; API