ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.865C>T (p.Gln289Ter) (rs121907999)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421016 SCV000520886 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing The Q289X nonsense variant in the ATP7B gene has been reported to be a common pathogenic variant in the Greek population and has been reported with severe, early-onset Wilson disease (Waldenström et al., 1996; Panagiotakaki et al., 2004; Manolaki et al., 2009; Behari et al., 2010). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000421016 SCV000610993 likely pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Invitae RCV000004068 SCV001209439 pathogenic Wilson disease 2019-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln289*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121907999, ExAC 0.006%). This variant has been observed in several individuals affected with Wilson disease and to segregate with disease in a family (PMID: 18403153, 19172127, 15845031, 15523622). ClinVar contains an entry for this variant (Variation ID: 3864). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000004068 SCV001361696 pathogenic Wilson disease 2019-07-16 criteria provided, single submitter clinical testing Variant summary: ATP7B c.865C>T (p.Gln289X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 248088 control chromosomes (gnomAD). c.865C>T has been reported in the literature in several homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Waldenstrom_1996, Panagiotakaki_2004, Manolaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004068 SCV000024234 pathogenic Wilson disease 2005-05-01 no assertion criteria provided literature only
Counsyl RCV000004068 SCV000220805 pathogenic Wilson disease 2017-12-15 no assertion criteria provided clinical testing

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