Submissions for variant NM_194248.3(OTOF):c.2374C>T (p.Arg792Trp)

gnomAD frequency: 0.00143  dbSNP: rs148532589

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151603	SCV000199786	likely benign	not specified	2015-04-24	criteria provided, single submitter	clinical testing	p.Arg792Trp in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (7/1598) of Finnish chromosome s and in 0.2% (65/28842) of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs148532589).
Illumina Laboratory Services, Illumina	RCV000294150	SCV000429627	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	RCV001704091	SCV000714450	likely benign	not provided	2020-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26969326, 30622556)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001704091	SCV003257879	likely benign	not provided	2024-07-19	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000294150	SCV005442620	pathogenic	Autosomal recessive nonsyndromic hearing loss 9	2024-12-26	criteria provided, single submitter	research	The OTOF c.2374C>T:p.(Arg792Trp) heterozygous variant was classified as pathogenic by Deafness Variation Database based on PMID: 26969326, 30622556. It was detected together with a novel OTOF variant, possibly deleterious and not found in gnomAD, c.3863C>T:p.(Ala1288Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151603	SCV005887385	likely benign	not specified	2025-01-13	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.2374C>T (p.Arg792Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 226676 control chromosomes, predominantly at a frequency of 0.0013 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 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011). c.2374C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss And Deafness without strong evidence for causality (e.g. Sloan-Heggen_2016, Tlili_2024). 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. The following publications have been ascertained in the context of this evaluation (PMID: 26969326, 38844983). ClinVar contains an entry for this variant (Variation ID: 164864). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004751295	SCV005351658	uncertain significance	OTOF-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The OTOF c.2374C>T variant is predicted to result in the amino acid substitution p.Arg792Trp. This variant has been reported along with a premature termination variant and two other rare missense variants in a patient with nonsyndromic hearing loss (Table S3, reported as NM_004802:c.133C>T, Sloan-Heggen et al. 2016. PubMed ID: 26969326) and was also reported without a second potentially causative variant in another patient with hearing loss (Morgan et al. 2018. PubMed ID: 30622556). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.