ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.2521G>A (p.Glu841Lys)

gnomAD frequency: 0.00001  dbSNP: rs772729658
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001762844 SCV001988774 uncertain significance not provided 2020-04-06 criteria provided, single submitter clinical testing 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: 26632695, 30482216)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323924 SCV004029958 uncertain significance not specified 2023-07-24 criteria provided, single submitter clinical testing Variant summary: OTOF c.2521G>A (p.Glu841Lys) results in a 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. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-05 in 243184 control chromosomes (gnomAD). c.2521G>A has been reported in the literature in individuals affected with auditory neuropathy spectrum disorder (e.g. Chang_2015, Wu_2018, Kim_2018, Kim_2021, Forli_2023). These data indicate that the variant may be associated with disease. 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: 26632695, 30482216, 34593925, 28766844, 31581539, 36837553). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001762844 SCV004292092 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 841 of the OTOF protein (p.Glu841Lys). This variant is present in population databases (rs772729658, gnomAD 0.02%). This missense change has been observed in individual(s) with auditory neuropathy (PMID: 26632695, 28766844, 30482216). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.E856K. ClinVar contains an entry for this variant (Variation ID: 1302777). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.