ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.4463A>T (p.Asp1488Val) (rs142284613)

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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 RCV000041544 SCV000065239 uncertain significance not specified 2018-11-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp1488Val va riant in the OTOF gene has been identified by our laboratory in 5 individuals wi th hearing loss, none of whom carried a second pathogenic variant in OTOF. This variant has also been identified in 0.13% (49/35440) of Latino chromosomes by gn omAD ( It has also been reported in ClinVar (V ariation ID 48235). Computational prediction tools and conservation analyses sug gest that the p.Asp1488Val variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, while the cl inical significance of the p.Asp1488Val variant is uncertain, its frequency in t he general population suggests that it is more likely to be benign. ACMG/AMP cri teria applied: BS1_Supporting, PP3.
GeneDx RCV000767001 SCV000620021 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing The D1488V variant in the OTOF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D1488V variant is observed in 20/11574 (0.17%) alleles from individuals of Latino background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The D1488V 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. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D1488V as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV001139029 SCV001299135 uncertain significance Deafness, autosomal recessive 9 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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