Submissions for variant NM_001292063.2(OTOG):c.3546C>A (p.Tyr1182Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
King Laboratory, University of Washington	RCV003155561	SCV003844131	pathogenic	Autosomal recessive nonsyndromic hearing loss 18B	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with an OTOG missense variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no other history of hearing loss. This variant is a nonsense that introduces a premature stop at position 1194 of 2925 in the OTOG protein. As of January 2023, this variant has not been reported to ClinVar and is found in 12 heterozygotes and 1 homozygote on gnomAD. Based on the prediction that this variant leads to a truncated protein and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005060992	SCV005698505	pathogenic	not provided	2024-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1194*) in the OTOG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). This variant is present in population databases (no rsID available, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with hearing impairment (PMID: 31581539). ClinVar contains an entry for this variant (Variation ID: 2445642). 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.