ClinVar Genomic variation as it relates to human health

in compound heterozygosis with a likely pathogenic missense variant in a patient with HL

OTOF c.4747C>T, p.R1583C alters a residue completely conserved in all sequenced vertebrates in a calcium-binding domain. A different substitution in the same codon (R1583H) is reported on ClinVar as pathogenic in compound heterozygosity with a nonsense mutation. R1583C is homozygous in 2 siblings with pre-lingual profound hearing loss in a Palestinan family (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 5/251474 alleles on gnomAD, all heterozygotes.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1583 of the OTOF protein (p.Arg1583Cys). This variant is present in population databases (rs781688103, gnomAD 0.004%). This missense change has been observed in individual(s) with OTOF-related conditions (PMID: 26818607, 33724713, 34424407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 402270). 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) performed at Invitae indicates that this missense variant is expected to disrupt OTOF protein function with a positive predictive value of 80%. 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: 24001616, 24053799, 31095577, 31827501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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: 34426522, 31589614, 33724713, 32747562, 26818607, 34424407, 24001616, 31827501, 36147510)

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive auditory neuropathy (MIM#601071) and deafness, 9 (MIM#601071). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (27 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 24 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C2 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg1583His) has been reported as likely pathogenic by an expert panel (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has multiple pathogenic reports in individuals with auditory neuropathy (ClinVar, PMIDs: 26818607, 33724713, 34652575). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

congenital, profound