ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.4747C>T (p.Arg1583Cys)

gnomAD frequency: 0.00002  dbSNP: rs781688103
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo RCV001730683 SCV001762968 pathogenic Bilateral sensorineural hearing impairment criteria provided, single submitter research in compound heterozygosis with a likely pathogenic missense variant in a patient with HL
King Laboratory, University of Washington RCV000454260 SCV001976387 likely pathogenic Autosomal recessive nonsyndromic hearing loss 9 2020-08-01 criteria provided, single submitter research 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.
Fulgent Genetics, Fulgent Genetics RCV000454260 SCV002782610 likely pathogenic Autosomal recessive nonsyndromic hearing loss 9 2021-12-27 criteria provided, single submitter clinical testing
Invitae RCV003558390 SCV004292077 pathogenic not provided 2023-10-25 criteria provided, single submitter clinical testing 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.
Hereditary Research Laboratory, Bethlehem University RCV000454260 SCV000538109 pathogenic Autosomal recessive nonsyndromic hearing loss 9 2016-06-04 no assertion criteria provided research congenital, profound

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