Submissions for variant NM_194248.3(OTOF):c.2348del (p.Gly783fs)

dbSNP: rs80356591

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211837	SCV000065185	pathogenic	Rare genetic deafness	2015-02-26	criteria provided, single submitter	clinical testing	The p.Gly783fs variant in OTOF has been reported in 2 siblings with auditory neu ropathy (Varga 2006) and has been identified by our laboratory in 1 individual w ith congenital hearing loss. All of these individuals were compound heterozygous . Data from large population studies are insufficient to assess the frequency of this variant. The p.Gly783fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 783 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant me ets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner (www.partners.org/personalizedmedicine/LMM) based upon its pre dicted impact on the protein.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	RCV001730476	SCV001762958	pathogenic	Bilateral sensorineural hearing impairment		criteria provided, single submitter	research	in compound heterozygosis with another frameshift variant, both likely pathogenic in patient with auditory neuropathy
Molecular Genetics, Royal Melbourne Hospital	RCV000021046	SCV002503775	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is a deletion of 1 bp in exon 20 (of 46) of OTOF that is predicted to create a premature termination codon at position 799, p.(Gly783Alafs*17), which is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism for disease for this gene. The variant is present in a large population cohort at a frequency of 0.005% (rs80356591, 12/262,222 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.02% in the African subpopulation (4/22,908 alleles, 0 homozygotes). The variant has been identified compound heterozygous with a second pathogenic allele in at least two individuals with non-syndromic auditory neuropathy (PMID: 16371502, 19461658). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PVS1, PM3_Strong.
Invitae	RCV002513157	SCV003524153	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly783Alafs*17) 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 (rs80356591, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of OTOF-related conditions (PMID: 16371502, 31980526). ClinVar contains an entry for this variant (Variation ID: 21834). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114200	SCV003801309	pathogenic	Nonsyndromic genetic hearing loss	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.2348delG (p.Gly783AlafsX17) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.2485C>T [p.Gln829Ter], c.2977_2978del [p.Gln994fs]). The variant allele was found at a frequency of 4.6e-05 in 262222 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (4.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.2348delG has been reported in the literature as a biallelic genotype in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Romanos_2009, Rodriguez-Ballesteros_2008, Baux_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews	RCV000021046	SCV000041700	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only