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

gnomAD frequency: 0.00001  dbSNP: rs111033349

Total submissions: 7

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 titute.org; 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