Submissions for variant NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter)

gnomAD frequency: 0.00004  dbSNP: rs80356593

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002227998	SCV002512132	pathogenic	Nonsyndromic genetic hearing loss	2022-05-13	reviewed by expert panel	curation	The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for Latino chromosomes in gnomAD v2.1.1, which meets the cutoff to apply BS1_Supporting. However, this variant has been established as a founder variant in the Spanish population and is thought to be causative in 3% of cases of deafness in the Spanish population (BS1_Supporting not applicable; PMID: 27177047). The p.Gln829Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 21/46 (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). The p.Gln829Ter variant has been identified in >50 patients with non-syndromic hearing loss (PM3_VeryStrong; PMIDs: 18381613, 17036997, 16371502, 14635104, 12114484). It has repeatedly been reported to segregate with hearing loss (PP1_Strong; PMIDs: 12114484, 14635104,16371502, 18381613). In addition to hearing loss, at least 24 patients reported to have the p.Gln829Ter variant presented with features of auditory neuropathy spectrum disorder, which is highly specific to OTOF and autosomal recessive hearing loss (PP4; PMIDs:18381613, 17036997, 14635104). In summary, the p.Gln829Ter 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, PP1_Strong, PM3_VeryStrong, PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211838	SCV000065196	pathogenic	Rare genetic deafness	2019-03-20	criteria provided, single submitter	clinical testing	The p.Gln829X variant in OTOF has been previously reported in >30 individuals with hearing loss or auditory neuropathy, all of whom were homozygous or compound heterozygous for a second pathogenic OTOF variant, and segregated in >10 affected relatives (Migliosi 2002, Rodriguez-Ballesteros 2003, Rodriguez-Ballesteros 2008, Varga 2006). This variant has been identified in 0.06% (22/34228) of Latino chromosomes by gnomAD, and has been reported to be a founder variant in the Spanish population based on linkage data (Migliosi 2002; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 829, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOF gene is an established disease mechanism in autosomal recessive auditory neuropathy spectrum disorder. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive auditory neuropathy spectrum disorder. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting.
GeneDx	RCV000325939	SCV000329902	pathogenic	not provided	2021-10-08	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: 16226319, 12114484, 25525159, 16371502, 31589614, 18381613, 14635104, 17036997, 31980526, 27177047, 33297549)
Invitae	RCV000325939	SCV001587436	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln829*) 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 (rs80356593, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with non-syndromic, prelingual sensorineural hearing loss (PMID: 12114484, 14635104, 16226319, 16371502, 17036997, 18381613). It is commonly reported in individuals of Spanish ancestry (PMID: 18381613). ClinVar contains an entry for this variant (Variation ID: 6137). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000325939	SCV002503161	pathogenic	not provided	2020-07-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006511	SCV003835879	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2022-12-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002227998	SCV004222718	pathogenic	Nonsyndromic genetic hearing loss	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.2485C>T (p.Gln829X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00017 in 243966 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00017 vs 0.0011), allowing no conclusion about variant significance. c.2485C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Rodriguez-Ballesteros_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18381613). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000006511	SCV000026694	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2006-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000006511	SCV000041704	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only