Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV001195283 | SCV001365592 | likely pathogenic | Rare genetic deafness | 2019-05-22 | criteria provided, single submitter | clinical testing | The p.Glu643X variant in OTOF has not been previously reported in individuals with hearing loss or auditory neuropathy spectrum disorder, but has been identified in 0.003% (1/25072) of Finnish chromosomes and in 0.002% (3/127636) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 643, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOF gene is an established disease mechanism in autosomal recessive auditory neuropathy spectrum disorder. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive auditory neuropathy spectrum disorder. ACMG/AMP Criteria applied: PVS1, PM2. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155368 | SCV003844336 | likely pathogenic | Nonsyndromic genetic hearing loss | 2023-02-28 | criteria provided, single submitter | clinical testing | Variant summary: OTOF c.1927G>T (p.Glu643X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249418 control chromosomes. To our knowledge, no occurrence of c.1927G>T in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV003679045 | SCV004400109 | pathogenic | not provided | 2023-11-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu643*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs200864338, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with OTOF-related conditions. ClinVar contains an entry for this variant (Variation ID: 929942). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |