Submissions for variant NM_194248.3(OTOF):c.2122C>T (p.Arg708Ter)

dbSNP: rs80356590

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002228049	SCV002512133	pathogenic	Nonsyndromic genetic hearing loss	2021-03-23	reviewed by expert panel	curation	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PP1_Strong; PMID: 14635104, 18381613, 26029705, 29434063, 19250381; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6).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neuropathy spectrum disorder, which is highly specific for OTOF (PP4; Partners Laboratory for Molecular Medicine unpublished data, ClinVar SCV000065176.6).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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211836	SCV000065176	pathogenic	Rare genetic deafness	2012-03-26	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV000760435	SCV000890318	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	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)
Molecular Genetics, Royal Melbourne Hospital	RCV000021043	SCV002503856	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2020-11-30	criteria provided, single submitter	clinical testing	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.
3billion	RCV000021043	SCV004013782	pathogenic	Autosomal recessive nonsyndromic hearing loss 9		criteria provided, single submitter	clinical testing	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.
Invitae	RCV000760435	SCV004332524	pathogenic	not provided	2023-11-11	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003894816	SCV004710100	pathogenic	OTOF-related condition	2024-02-20	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000021043	SCV000041697	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only
Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research	RCV000021043	SCV001448680	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2020-02-15	no assertion criteria provided	research	Candidate homozygous variant segregating well with the disease phenotype
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291117	SCV001479483	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research