ClinVar Miner

Submissions for variant NM_004086.3(COCH):c.271C>T (p.Arg91Ter)

gnomAD frequency: 0.00002  dbSNP: rs540895576
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002517536 SCV003284183 pathogenic not provided 2022-06-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg91*) in the COCH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COCH are known to be pathogenic (PMID: 29449721, 31126177). This variant is present in population databases (rs540895576, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COCH-related conditions. ClinVar contains an entry for this variant (Variation ID: 228524). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV003447518 SCV004175743 likely pathogenic Hearing loss, autosomal recessive 110 2023-02-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000220930 SCV000271591 uncertain significance not specified 2015-12-04 flagged submission clinical testing The p.Arg91X variant in COCH has not been previously reported in individuals wit h hearing loss, but has been identified in 4/66738 European chromosomes, 1/10406 of African chromosomes and 1/8652 in East Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs540895576). This nonsense variant leads to a premature termination codon at position 91 in exon 4 (of 12 exons), and is predicted to undergo nonsense-mediated mRNA decay leadin g to an absent protein. To date, only missense and small in-frame deletion varia nts have been reported as causative for hearing loss, which suggests a gain-of-f unction mechanism (Bae 2014). However, there is limited functional data to suppo rt this as an established disease mechanism for this gene and the impact of loss of function variants is currently unknown. In summary, the clinical significanc e of the p.Arg91X variant is uncertain.

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