ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.4023+1G>A (rs186810296)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041538 SCV000065233 uncertain significance not specified 2019-09-25 criteria provided, single submitter clinical testing The c.4023+1G>A variant in OTOF has been reported in at least 5 individuals with hearing loss, including 1 homozygote and 1 compound heterozygote (Wang 2011, Zhang 2016, Iwasa 2019, LMM unpublished data). However, two individuals had alternate explanations of the hearing loss identified (Iwasa 2019, LMM unpublished data). It has also been identified in >1% (235/19950) of East Asian chromosomes by gnomAD ( For this reason it has been reported in the literature as uncertain or benign (Shearer 2014, Azaiez 2018, DiStefano 2018). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing. However, this exon is in-frame and computational prediction tools suggest that alternative splice donor sites would result in in-frame retention of intronic bases. Therefore, it is uncertain if this variant would lead to a truncated or absent protein. In summary, the clinical significance of this variant is uncertain due to the conflicting evidence, which includes its high frequency and uncertain splicing impact. ACMG/AMP criteria applied: BA1, PP3, PM3.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490336 SCV000267430 pathogenic Deafness, autosomal recessive 9 2016-03-18 criteria provided, single submitter reference population
Invitae RCV000897451 SCV001041596 benign not provided 2018-03-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000490336 SCV001302002 uncertain significance Deafness, autosomal recessive 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.

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