ClinVar Genomic variation as it relates to human health

The c.4748G>A variant in OTOF is a missense variant predicted to cause substitution of arginine by histidine at amino acid 1583. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16254 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 0.912, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). Another missense variant c.4747C>T (p.R1583C) (PMID:26818607, 31589614, 32747562, 33724713, 34426522, ClinVar Variation ID:402270) in the same codon has been classified as pathogenic/likely pathogenic for autosomal recessive nonsyndromic hearing loss in ClinVar (PM5). At least one patient with this variant and compound heterozygous for the c.2215-1G>C variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for ANSD (PP4, PMID:24001616). This variant has been detected in at least 1 individual with ANSD, who was compound heterozygous for the variant and a pathogenic or likely pathogenic variant were confirmed in trans by family testing (c.2215-1G>C, 1 PM3 point, PMID:24001616). Additional compound heterozygous cases with variants c.5816G>A (p.R1939Q), c.3515G>A (p.R1172Q), and c.2523+1G>T (PMIDs: 24053799, 31095577, 31827501 respectively) were also seen, but excluded from scoring due to less scorable evidence. 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, PM5, PP4, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 7/21/2022).

Observed in other unrelated patients with hearing loss in published literature (Iwasa et al., 2013; Iwasa et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24053799, 31095577, 31827501, 24001616)

Variant summary: OTOF c.4748G>A (p.Arg1583His) results in a non-conservative amino acid change located in the sixth C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes (gnomAD). c.4748G>A has been reported in the literature in at least four compound heterozygous individuals affected with Nonsyndromic Hearing Loss and Deafness, Type 9 (Iwasa_2013, Zhang_2013, Qiu_2019, Iwasa_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24001616, 24053799, 31095577, 31827501). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1583 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26818607, 32747562, 33724713, 34424407). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OTOF protein function. ClinVar contains an entry for this variant (Variation ID: 2429109). This missense change has been observed in individual(s) with auditory neuropathy and/or clinical features of OTOF-related conditions (PMID: 24001616, 24053799, 31095577, 31827501). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs139416718, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1583 of the OTOF protein (p.Arg1583His).