Submissions for variant NM_194248.3(OTOF):c.245G>A (p.Arg82His)

gnomAD frequency: 0.00237  dbSNP: rs149766574

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041499	SCV000065194	benign	not specified	2012-05-16	criteria provided, single submitter	clinical testing	Arg82His in Exon 04 of OTOF: This variant is not expected to have clinical signi ficance because it has been identified in 0.6% (24/3738) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs149766574).
Illumina Laboratory Services, Illumina	RCV000785039	SCV000429656	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000767023	SCV000620270	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	The R82H variant in the OTOF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It is reported as benign in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000065194.4; Landrum et al., 2015). The R82H variant is observed in 50/7412 (0.68%) alleles from individuals of African background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The R82H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R82H as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000041499	SCV000860989	likely benign	not specified	2018-04-30	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000785039	SCV000923592	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000767023	SCV001039162	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001543606	SCV001519356	uncertain significance	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
CeGaT Center for Human Genetics Tuebingen	RCV000767023	SCV004140963	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	OTOF: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003924989	SCV004750287	likely benign	OTOF-related disorder	2019-12-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).