ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.2239G>T (p.Glu747Ter) (rs397515591)

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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 RCV000211840 SCV000199794 pathogenic Rare genetic deafness 2017-05-04 criteria provided, single submitter clinical testing The p.Glu747X variant in OTOF has been reported in the homozygous state in four individuals with hearing loss, including 1 individual with auditory neuropathy b ased on the presence of otoacoustic emissions (Rodriguez-Ballesteros 2008 and LM M data). This variant has been identified in 1/33574 Latino chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs39 7515591); however, this frequency is low enough to be consistent with a recessiv e carrier frequency for hearing loss. This nonsense variant leads to a prematur e termination codon at position 747, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive auditory neuropathy spectrum disorder, based on the predicted impact to the protein, reported homozygosity in multiple affected individuals with consistent specific phenotypes, and the low frequency in the g eneral population.
GeneDx RCV000318963 SCV000329896 pathogenic not provided 2016-03-31 criteria provided, single submitter clinical testing The E747X pathogenic variant in the OTOF gene has been reported previously in the homozygous state in a Libyan individual with profound prelingual sensorineural hearing loss (Rodríguez-Ballesteros et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E747X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret E747X as a pathogenic variant.
GeneReviews RCV000056026 SCV000087086 pathologic Deafness, autosomal recessive 9 2011-04-26 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000056026 SCV000804277 pathogenic Deafness, autosomal recessive 9 2008-06-01 no assertion criteria provided literature only

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