Submissions for variant NM_194248.3(OTOF):c.5038C>T (p.Arg1680Cys)

gnomAD frequency: 0.00044  dbSNP: rs147070644

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041558	SCV000065253	uncertain significance	not specified	2016-06-30	criteria provided, single submitter	clinical testing	The p.Arg1680Cys variant in OTOF has now been identified by our laboratory in th e heterozygous state in 2 individuals with hearing loss, but a second variant af fecting the remaining copy of the gene has not been found in of either individua l. This variant has also been identified in 0.1% (60/65886) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs147070644). Although this variant has been seen in the general populatio n, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1680Cys variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001143361	SCV001303882	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.
Invitae	RCV001852850	SCV002286894	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001143361	SCV002778825	uncertain significance	Autosomal recessive nonsyndromic hearing loss 9	2021-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041558	SCV003844959	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: OTOF c.5038C>T (p.Arg1680Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 250712 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00041 vs 0.0011), allowing no conclusion about variant significance. c.5038C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss, however without strong evidence for causality (e.g., Sloan-Heggen_2016). Additionally, one ClinVar submitter reports identifying the variant in at least two heterozygous individuals with hearing loss, however, no second OTOF variant was identified (Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine). These reports do not provide 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. Four ClinVar submitters (evaluation after 2014) have cited the variant, with three submitters classifying the variant as uncertain significance and one submitter classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.