Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ATP7B : Wilson disease

HGNC:870 | MONDO_0010200
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: General Gene Curation
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 4
Bull PC et al. 1993 Dec (PMID:8298639); Duc HH et al. 1998 Nov-Dec (PMID:9887381); Beyersdorff A et al. 2006 Apr (PMID:16635921);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
Duc HH et al. 1998 Nov-Dec (PMID:9887381); Gu S et al. 2013 July 02 (PMID:23843956);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 0.6 1
Gu S et al. 2013 July 02 (PMID:23843956);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 0.6    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Harris ED et al. 2000 (PMID:10940336);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 0.5
Bull PC et al. 1993 Dec (PMID:8298639); GTEx Consortium et al. 2013 Jun (PMID:23715323);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 2 1
Gu S et al. 2013 July 02 (PMID:23843956); Payne AS et al. 1998 Sep 01 (PMID:9724794);
Models Non-human model organism 2 0 - 4 4 1 2 4
Buiakova OI et al. 1999 Sep (PMID:10441329);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Terada K et al. 1998 Jan 16 (PMID:9430732);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
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.