ClinVar Miner

Submissions for variant NM_001292063.1(OTOG):c.499del (p.Val167fs) (rs876657657)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000218007 SCV000271254 likely pathogenic Rare genetic deafness 2016-02-04 criteria provided, single submitter clinical testing The p.Val179fs variant in OTOG has not been previously reported in individuals w ith hearing loss. This variant has been identified in 1/722 of African chromosom es by the Exome Aggregation Consortium (ExAC,; h owever, this frequency is low enough to be consistent with a recessive carrier f requency. This variant is predicted to cause a frameshift, which alters the prot ein?s amino acid sequence beginning at position 179 and leads to a premature ter mination codon 53 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Two loss of function variants in the OTOG gene have been reported to segregate with hearing loss in two families (Schrader s 2012), and disruption of Otog in mice resulted in deafness supporting of a los s-of-function mechanism for the disease (Simmler 2000). While these two studies provide evidence of a causative link between loss of function of OTOG and autoso mal recessive hearing loss, to date, no other publications report on OTOG varian ts in individuals with hearing loss. In summary, although additional evidence is required to strengthen the gene-disease association for OTOG and hearing loss, the current data supports a likely pathogenic role for the p.Val179fs variant.
GeneDx RCV000487342 SCV000573779 pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing The c.535delG variant in the OTOG gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.535delG variant causes a frameshift starting with codon Valine 179, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Val179TrpfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Adequate data is not available in large population cohorts to assess the frequency of this variant in publicly available databases; however, this variant has not been detected at a significant frequency in presumably healthy individuals tested at GeneDx. We interpret c.535delG as a pathogenic variant.
Athena Diagnostics Inc RCV000487342 SCV000842986 likely pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing

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