ClinVar Miner

Submissions for variant NM_194248.2(OTOF):c.1544T>C (p.Ile515Thr) (rs80356586)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000021035 SCV000041689 association Deafness, autosomal recessive 9 2015-07-30 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000604852 SCV000710845 likely pathogenic Nonsyndromic hearing loss and deafness 2017-02-14 criteria provided, single submitter clinical testing The p.Ile515Thr (NM_194248.2 c.1544T>C, ClinVar Variation ID#6143) variant in OTOF has been reported in 1 compound heterozygous individual with hearing loss who had a temperature-sensitive auditory neuropathy phenotype, in trans with a nonsense variant, and segregated with disease in an affected family member (Varga 2006, Strenzke 2016, Avraham 2016). This variant has also been reported in 1 homozygous individual with hearing loss and in 3 affected homozygous family members, who all had a second missense OTOF variant of uncertain significance in cis (Mirghomizadeh 2002). A knock-in mouse model homozygous for the p.Ile515Thr variant was shown to have hearing loss (Strenzke 2016). This variant has also been identified in 0.002% (1/65,772) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356586). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Ile515Thr variant is likely pathogenic for OTOF-related hearing loss in an autosomal recessive manner based upon biallelic observations in patients, low frequency in controls, and an animal model.
OMIM RCV000006517 SCV000026700 pathogenic Auditory neuropathy, autosomal recessive, 1 2006-07-01 no assertion criteria provided literature only
OMIM RCV000021035 SCV000222658 pathogenic Deafness, autosomal recessive 9 2006-07-01 no assertion criteria provided literature only

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