ClinVar Miner

Submissions for variant NM_194248.2(OTOF):c.5098G>C (rs199766465)

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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 RCV000211734 SCV000065260 uncertain significance not specified 2017-06-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1700Gl n variant in OTOF has been reported in 9 individuals with hearing loss, with 6 o f these individuals had clinical features of auditory neuropathy spectrum disord er (ANSD; Chiu 2010, LMM data). Six of the individuals with features of ANSD wer e homozygous for this variant, and in one family this variant segregated in an a ffected sibling. The remaining 3 individuals were heterozygous for the variant, and one of these heterozygotes carried a pathogenic variant in a different gene (Chiu 2010). However, this variant has also been identified in 0.7% (127/18854) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs199766465). Computational prediction tools and c onservation analysis suggest that the p.Glu1700Gln variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, due to it's rel atively high frequency in the East Asians population, the lack of a significant number of segregations in families, or lack of affected individuals who are comp ound heterozygous for p.Glu1700Gln with a second clearly pathogenic OTOF variant , the clinical significance of the p.Glu1700Gln variant is uncertain.
GeneDx RCV000413616 SCV000490937 likely pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing The E1700Q variant in the OTOF gene has been reported previously in association with auditory neuropathy, in affected individuals from Taiwan who were homozygous for the E1700Q variant. Based on a shared common haplotype, the authors suggest a founder effect for E1700Q in the Taiwanese population (Chiu et al., 2010). Although not present in the homozygous state, the E1700Q variant was observed on 64/8614 (0.74%) alleles from individuals of East Asian background in the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare variant in this population. The E1700Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The E1700Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV000056047 SCV000915907 pathogenic Deafness, autosomal recessive 9 2018-11-05 criteria provided, single submitter clinical testing Across a selection of availabe literature, the OTOF c.5098G>C (p.Glu1700Gln) variant has been reported in at least three studies and is found in at least 21 probands including at least eight in a homozygous state, eight in a compound heterozygous state, and three in a heterozygous state (Chiu et al. 2010; Wu et al. 2011; Wu et al. 2018). The p.Glu1700Gln variant is described as founder variant that has been seen in up to 20% of Taiwanese auditory neuropathy/auditory dys-synchrony probands (Jin et al. 2014). The p.Glu1700Gln variant was absent from 100 ethnically-matched control individuals and is reported at a frequency of 0.007430 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Glu1700Gln variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneReviews RCV000056047 SCV000087107 pathologic Deafness, autosomal recessive 9 2011-04-26 no assertion criteria provided curation Converted during submission to Pathogenic.

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