Submissions for variant NM_194248.3(OTOF):c.2381G>A (p.Arg794His)

gnomAD frequency: 0.00122  dbSNP: rs80356592

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041494	SCV000065189	likely benign	not specified	2015-08-06	criteria provided, single submitter	clinical testing	p.Arg794His in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (71/26210) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356592).
Invitae	RCV000955909	SCV001102646	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000021047	SCV001135637	likely benign	Autosomal recessive nonsyndromic hearing loss 9	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000021047	SCV001296880	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Athena Diagnostics Inc	RCV000955909	SCV001476589	likely benign	not provided	2020-08-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000955909	SCV002498533	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	OTOF: PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041494	SCV002571056	likely benign	not specified	2022-07-08	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.2381G>A (p.Arg794His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 220574 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2381G>A has been found in the heterozygous state (with no second OTOF variant reported) in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Schrauwen_2013). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneReviews	RCV000021047	SCV000041701	not provided	Autosomal recessive nonsyndromic hearing loss 9		no assertion provided	literature only