ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.524_525del (p.Lys175fs) (rs558037268)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169375 SCV000220755 likely pathogenic Wilson disease 2014-09-30 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169375 SCV000694467 likely pathogenic Wilson disease 2021-02-03 criteria provided, single submitter clinical testing Variant summary: ATP7B c.524_525delAA (p.Lys175SerfsX28) 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. The variant was absent in 249292 control chromosomes. c.524_525delAA has been reported in the literature in at-least one individual affected with Wilson Disease (example, Collin_2007, unpublished abstract), and has been subsequently cited in the Wilson Disease database and as a non-primary evidence in a published report (Singh_2019). Of note, a different nucleotide change, namely c.525_526delAG, that would result in the same translational impact at the protein level (i.e., p.Lys175SerfsX28) has also been reported (Coffee_2013, Curtis_1999). Other publications in the field do not allow accurate distinction between these two variants due to ambiguously reported annotation's that do not specify the exact nucleotide change. Therefore, these data do not allow a firm conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000169375 SCV000752247 pathogenic Wilson disease 2019-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys175Serfs*28) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Wilson disease (PMID: 17680703). ClinVar contains an entry for this variant (Variation ID: 188995). Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169375 SCV001470912 pathogenic Wilson disease 2020-08-21 criteria provided, single submitter clinical testing The ATP7B c.524_525delAA; p.Lys175fs variant (rs558037268) is reported in the literature in an individual affected with Wilson disease (University of Alberta database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function in ATP7B is a known mechanism of disease and truncating variants downstream of c.524_525delAA have been reported in individuals with Wilson disease and are considered pathogenic (University of Alberta database and references therein). Based on available information, the c.524_525delAA variant is considered to be pathogenic. References: University of Alberta Wilson Disease database:
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001291604 SCV001480156 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing

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