ClinVar

Description

Variant summary: OTOF c.5098G>C (p.Glu1700Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 249992 control chromosomes, predominantly at a frequency of 0.0069 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.5098G>C has been reported in the literature as a frequent founder variant in the Taiwanese population (example, Chiu_2010), and as homozygous and compound heterozygous genotypes in individuals of East Asian ethnicity (EAS) from many simplex families affected with auditory neuropathy spectrum disorder (ANSD) (example, Chiu_2010, Lee_2014, Chen_2018, Qiu_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Pathogenic, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.