ClinVar Miner

Submissions for variant NM_194248.3(OTOF):c.2485C>T (p.Gln829Ter) (rs80356593)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211838 SCV000065196 pathogenic Rare genetic deafness 2019-03-20 criteria provided, single submitter clinical testing The p.Gln829X variant in OTOF has been previously reported in >30 individuals with hearing loss or auditory neuropathy, all of whom were homozygous or compound heterozygous for a second pathogenic OTOF variant, and segregated in >10 affected relatives (Migliosi 2002, Rodriguez-Ballesteros 2003, Rodriguez-Ballesteros 2008, Varga 2006). This variant has been identified in 0.06% (22/34228) of Latino chromosomes by gnomAD, and has been reported to be a founder variant in the Spanish population based on linkage data (Migliosi 2002; http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 829, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOF gene is an established disease mechanism in autosomal recessive auditory neuropathy spectrum disorder. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive auditory neuropathy spectrum disorder. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting.
GeneDx RCV000325939 SCV000329902 pathogenic not provided 2016-06-29 criteria provided, single submitter clinical testing The Q829X pathogenic variant in the OTOF gene was first reported in the homozygous state in multiple individuals of Spanish and Cuban descent with nonsyndromic hearing loss (Migliosi et al., 2002). The Q829X variant was not found in 200 unrelated Spanish controls with normal hearing and heterozygous carriers were unaffected (Migliosi et al., 2002). This variant has since been reported in the compound heterozygous state in numerous other Spanish individuals with nonsyndromic hearing loss (Rodríguez-Ballesteros et al., 2003; Varga et al., 2006; Rodríguez-Ballesteros et al., 2008). The Q829X variant is reported as the third most common pathogenic variant causing prelingual deafness in the Spanish population, with approximately 3% of Spanish individuals with autosomal recessive hearing loss having this variant (Rodríguez-Ballesteros et al., 2003; Rodríguez-Ballesteros et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret Q829X as a pathogenic variant
OMIM RCV000006511 SCV000026694 pathogenic Deafness, autosomal recessive 9 2006-07-01 no assertion criteria provided literature only
GeneReviews RCV000006511 SCV000041704 association Deafness, autosomal recessive 9 2015-07-30 no assertion criteria provided literature only

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