ClinVar Miner

Submissions for variant NM_001277269.1(OTOG):c.2500C>T (p.Gln834Ter) (rs554847663)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578779 SCV000680934 pathogenic not provided 2021-05-18 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33105617, 32860223, 29907799, 10655058)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000616086 SCV000712161 pathogenic Rare genetic deafness 2020-04-14 criteria provided, single submitter clinical testing The p.Gln834X variant in OTOG has been identified in 4 individuals with hearing loss: 2 heterozygotes where a second variant was not identified on the other copy of OTOG, in 1 homozygote, and in 1 compound heterozygote with a second pathogenic OTOG variant (Sheppard 2018 PMID: 29907799, LMM data). Both variants segregated with hearing loss in an affected sibling (LMM data). The p.Gln834X variant has also been reported by other clinical laboratories in ClinVar (Variation ID 417941) and has been identified in 0.12% (8/6636) of Ashkenazi Jewish and in 0.08% (51/60760) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 834, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOG gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3, PP1, BS1_Supporting.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000578779 SCV000891954 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000477813 SCV000893872 likely pathogenic Deafness, autosomal recessive 18b 2018-10-31 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV001007897 SCV001167603 likely pathogenic Seizures; Intellectual disability 2019-02-07 criteria provided, single submitter clinical testing
Invitae RCV000578779 SCV001206868 pathogenic not provided 2019-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln834*) in the OTOG gene. It is expected to result in an absent or disrupted protein product. While this variant is present in population databases (rs554847663), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 417941). Loss-of-function variants in OTOG are known to be pathogenic (PMID: 23122587). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000477813 SCV001870382 pathogenic Deafness, autosomal recessive 18b 2021-07-22 criteria provided, single submitter research ACMG codes:PVS1, PM2, PP5
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477813 SCV000536895 likely pathogenic Deafness, autosomal recessive 18b 2016-07-19 no assertion criteria provided research

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