The relationship between ATP7B and Wilson disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of March 26th, 2019. Variants in ATP7B were first reported in humans with this disease as early as 1993 (Bull et al., PMID 8298639). Wilson disease is a disorder of copper metabolism characterized by an accumulation of copper in many organs, particularly the liver and brain. At least 700 unique germline variants have been identified (missense, nonsense, splice site, frameshift) (reviewed in Członkowska et al., 2018; PMID 30190489). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. The mutational mechanism for disease is loss of function leading to reduced (or absent) copper-transporter activity (Huster et al., 2012; PMID 22240481). This gene-disease association is supported by expression studies, in vitro functional assays, and animal models. In summary, ATP7B is definitively associated with autosomal recessive Wilson disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on March 27, 2019.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.