ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.19_20del (p.Gln7fs) (rs749363958)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478984 SCV000567525 pathogenic not provided 2015-09-01 criteria provided, single submitter clinical testing The c.19_20delCA pathogenic variant in the ATP7B gene has been reported previously in a singleindividual with Wilson disease (Vrabelova et al., 2005). The c.19_20delCA variant causes a frameshiftstarting with codon Glutamine 7, changes this amino acid to an Aspartic Acid residue, and creates apremature Stop codon at position 14 of the new reading frame, denoted p.Q7DfsX14. This variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.19_20delCA variant was not observed in approximately 6,200individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. We interpret c.19_20delCA as apathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000478984 SCV000602607 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing
Counsyl RCV000576360 SCV000678019 uncertain significance Wilson disease 2017-05-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576360 SCV000918583 likely pathogenic Wilson disease 2018-10-15 criteria provided, single submitter clinical testing Variant summary: ATP7B c.19_20delCA (p.Gln7AspfsX14) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.314C>A, p.Ser105X; c.525dupA, p.Val176fsX28; c.778dupC, p.Gln260fsX10). The variant allele was found at a frequency of 0.00014 in 277202 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00014 vs 0.0054), allowing no conclusion about variant significance. The variant, c.19_20delCA, has been reported in the literature in individuals affected with Wilson Disease (Vrabelova_2005, Gialluisi_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000576360 SCV000939965 pathogenic Wilson disease 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln7Aspfs*14) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs749363958, ExAC 0.03%). This variant has been observed in an individual affected with Wilson disease (PMID: 15967699). ClinVar contains an entry for this variant (Variation ID: 419611). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.

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