ClinVar Miner

Submissions for variant NM_001292063.2(OTOG):c.8018_8019delinsAT (p.Ala2673Asp) (rs876657945)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000221473 SCV000272267 uncertain significance not specified 2016-03-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala2685Asp va riant in OTOG has been previously reported by our laboratory in one individual w ith hearing loss, in whom a variant affecting the remaining copy of the gene was not identified. Although the coding change identified in this individual (c.805 4_8055delinsAT) was not reported in large population databases, the two componen t variants, c.8054C>A and c.8055C>T were reported in 1/4874 and 1/4880 European chromosomes, respectively, by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs563948391 and rs531303093). While these variants a re likely to represent the c.8054_8055delinsAT variant, at this time we cannot c onfirm that the two variants were identified on the same chromosome in the ExAC cohort. Furthermore, alanine (Ala) at position 2685 is conserved in mammals but not in evolutionarily distant species, with >15 species of birds carry an aspart ic acid (Asp) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide strong evide nce for or against an impact to the protein. In summary, while the clinical sign ificance of the p.Ala2685Asp variant is uncertain, the conservation data suggest s that it is more likely to be benign.
GeneDx RCV000767213 SCV000710181 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing The c.8054_8055delCCinsAT variant in the OTOG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.8054_8055delCCinsAT variant results in the replacement of the normal Alanine at position 2685 with an Aspartic Acid, denoted p.A2685D. The c.8054_8055delCCinsAT variant is not observed in large population cohorts (Lek et al., 2016). The c.8054_8055delCCinsAT variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret c.8054_8055delCCinsAT as a variant of uncertain significance.

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