ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.5375G>A (p.Arg1792His)

gnomAD frequency: 0.00001  dbSNP: rs111033349
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000041571 SCV000065266 likely pathogenic Rare genetic deafness 2016-12-08 criteria provided, single submitter clinical testing The p.Arg1792His variant in OTOF has been previously reported by our laboratory in 3 individuals with hearing loss, including two homozygotes and one with audit ory neuropathy spectrum disorder (ANSD) who was compound heterozygous for a seco nd pathogenic variant in OTOF. This variant has been reported in 1/11258 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins; dbSNP rs111033349); however, its frequency is low enough to be consi stent with a recessive carrier frequency. Computational prediction tools and con servation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant is likely pathogenic for autosomal recessive hearing loss.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171287 SCV000221484 likely pathogenic not provided criteria provided, single submitter research
GeneDx RCV000171287 SCV002526636 likely pathogenic not provided 2021-12-21 criteria provided, single submitter clinical testing 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: 27124789, 29048421, 31095577)
Invitae RCV000171287 SCV004292075 pathogenic not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1792 of the OTOF protein (p.Arg1792His). This variant is present in population databases (rs111033349, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive OTOF-related conditions (PMID: 29048421, 31095577, 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: 48259). 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. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31095577, 34416374, 34536124; Invitae). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000656336 SCV004804932 pathogenic Autosomal recessive nonsyndromic hearing loss 9 2024-03-17 criteria provided, single submitter research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000656336 SCV000778299 likely pathogenic Autosomal recessive nonsyndromic hearing loss 9 2018-02-13 no assertion criteria provided clinical testing
OMIM RCV000656336 SCV000804276 pathogenic Autosomal recessive nonsyndromic hearing loss 9 2018-08-31 no assertion criteria provided literature only

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