The c.5374C>T variant in OTOF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1792. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16256 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). 1 different missense variant, c.5375G>A (p.R1792H) (PMID: 29048421, ClinVar Variation ID: 48259), in the same codon has been classified as likely pathogenic for nonsyndromic hearing loss by multiple submitters in ClinVar (PM5). This variant has been detected in at least 3 individuals with AR deafness. For two of those individuals, both were compound heterozygous for the variant and a VUS meeting PM2_Supporting, and both of those were confirmed in trans by family testing (c.2676G>A (p.K892K) which occurs at the last nucleotide in exon (22) of OTOF and c.4748G>A (p.R1583H), 1.5 PM3 points, PMID: 34416374, Universitätsmedizin Göttingen, Institute of Human Genetics/Institute of Auditory Neuroscience & InnerEarLab) (PM3). ​​At least one patient was compound heterozygous for this variant and the p.K892K variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for autosomal recessive deafness (PP4, PMID: 34416374). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3, PM5 (ClinGen Hearing Loss VCEP specifications version 2; 6/27/2022).