Submissions for variant NM_144672.4(OTOA):c.2359G>T (p.Glu787Ter)

gnomAD frequency: 0.00927  dbSNP: rs200988634

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202954	SCV000258245	uncertain significance	not specified	2015-05-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764038	SCV000894992	uncertain significance	Autosomal recessive nonsyndromic hearing loss 22	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825538	SCV000966854	pathogenic	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The c.2359G>T, p.Glu787X variant in OTOA is a nonsense variant leads to a premature termination codon at position 787, which is predicted to lead to a truncated or absent protein. Of note, the OTOA gene has a pseudogene (OTOAP1, loc653786) that contains this nucleotide variant as the reference base (GrCH37 chr16:22563762) in humans. As such, the p.Glu787X variant requires long range PCR to determine whether the variant exists in the OTOA or OTOAP1 gene. This variant has been identified in 1 individual by our laboratory who harbored a deletion of the OTOA gene on the remaining allele, and the p.Glu787X variant was confirmed by long range PCR in both the proband and an unaffected parent. Furthermore, the variant has been previously reported in 2 individual with hearing loss who carried a second pathogenic variang in OTOA, and in the heterozygous state in 1 healthy individual (Gao 2013 PMID: 23690975, Lindor 2015 PMID: 26434960, Laurent 2021 PMID: 33492714); one of the studies performed long range PCR to confirm the presence of the variant in the gene. This variant has also been reported in 1% (165/16068) of East Asian chromosomes by gnomAD; however, it failed the sequencing quality metric filter in this database and thus contamination from the pseudogene cannot be ruled out for those individuals (http://gnomad.broadinstitute.org). As such, the population frequency of this variant is unknown. Loss of function of the OTOA gene is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss, provided that it is confirmed to be present in the OTOA gene and not the OTOAP1 pseudogene. ACMG/AMP Criteria applied: PVS1, PM3_S.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000202954	SCV001251815	uncertain significance	not specified	2020-05-03	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000764038	SCV001984642	pathogenic	Autosomal recessive nonsyndromic hearing loss 22	2021-01-25	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000764038	SCV001994816	pathogenic	Autosomal recessive nonsyndromic hearing loss 22	2021-10-28	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000764038	SCV002073146	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 22		criteria provided, single submitter	clinical testing	The stop gained p.E787* in OTOA (NM_144672.4) has been previously reported in affected individuals (Lindor et al, 2015). The variant is present in OTOP which overlaps with a pseudogene and hence currently without confirmation via long rage PCR and sanger it is not possible to predict if the variant arises from the gene or pseudogene. The variant is present in gnomAD database but has been flagged as having low sequencing quality and may not represent true frequency. The variant has been submitted to ClinVar as Likey Pathogenic/ Uncertain significance. If confirmed to be present in the gene OTOA, it is predicted to cause protein truncation. Loss of function variants have been previousy reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000764038	SCV004100193	pathogenic	Autosomal recessive nonsyndromic hearing loss 22	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: OTOA c.2359G>T (p.Glu787X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00031 in 243820 control chromosomes (gnomAD). c.2359G>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss or unilateral auditory neuropathy (van Beeck Calkoen_2019, Song_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34175691, 31152317). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.