ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.5332G>T (p.Val1778Phe) (rs111033330)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757590 SCV000885879 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing The p.Val1778Phe variant (rs111033330) has been previously reported in association with auditory neuropathy in an Ashkenazi Jewish family (Fedick 2016). Fedick et al reported 4 siblings homozygous for the p.Val1778Phe variant with highly variable degrees of hearing loss (mild to moderately -severe) and auditory brainstem response testing consistent with auditory neuropathy/dys-synchrony. This variant has been reported to ClinVar (Variation ID: 48258) and according to information provided by Fedick et al the entry from Partners HealthCare represents a 2nd Jewish family with the p.Val1778Phe variant in trans with a known pathogenic variant, but that information is not available on ClinVar. The p.Val1778Phe variant is predicted to be more frequent in Ashkenazi Jewish individuals than in other populations with an estimated frequency of 0.4 - 1.27 percent (gnomAD, and Fedick 2016). Altogether, there is not enough evidence to classify the p.Val1778Phe variant with certainty.
Illumina Clinical Services Laboratory,Illumina RCV000779323 SCV000915906 uncertain significance Deafness, autosomal recessive 9 2018-03-19 criteria provided, single submitter clinical testing The OTOF c.5332G>T (p.Val1778Phe) variant has been reported in one study in which it was found in a homozygous state in four siblings affected with an autosomal recessive form of nonsyndromic sensorineural hearing loss, and in a heterozygous state in both parents and four unaffected siblings (Fedick et al. 2016). The affected individuals exhibited a variable degree of hearing loss from mild to moderately severe. The p.Val1778Phe variant was found in 13 of 1021 Ashkenazi Jewish controls and determined to have a carrier frequency of 1.27%, suggesting a founder variant, and is reported at a frequency of 0.004827 in the Ashkenazi Jewish population of the Genome Aggregation Database. The valine residue at this position is in a highly conserved region (Fedick et al. 2016). A second variant has been reported in a heterozygous state in one Japanese individual affected with hearing loss, at the same nucleotide position (c.5332G>A) resulting in substitution of the valine residue with isoleucine (Iwasa et al. 2013). Based on the evidence, the p.Val1778Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041570 SCV000065265 likely pathogenic Nonsyndromic hearing loss and deafness 2015-10-29 criteria provided, single submitter clinical testing

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