Gene Validity Curation

PKP2 - arrhythmogenic right ventricular cardiomyopathy

Gene: PKP2 (HGNC:9024)
Classification - 03/08/2018
Disease: arrhythmogenic right ventricular cardiomyopathy (MONDO_0016587)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy Contributors:
  • UNC Biocuration Core (secondary contributor)
Evidence Summary: The relationship between PKP2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in PKP2 were first reported in humans with this disease as early as 2004 (Gerull et al., PMID: 15489853). PKP2 is the major causative gene for ARVC and accounts for 34%-74% of cases (McNAlly et al., 2005; PMID: 20301310). There are over 250 PKP2 variants listed in ClinVar for ARVC (missense, nonsense, frameshift, complex rearrangements, etc) (Novelli et al., 2018; PMID: 30619891). 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. This gene-disease relationship is supported by animal models, in vitro assays, and protein interactions. In summary, PKP2 is definitively associated with autosomal dominant ARVC. 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 Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October, 26, 2018 (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 17 25.5 10
Gerull B et al. 2004 Nov (PMID:15489853); Syrris P et al. 2006 Jan 24 (PMID:16415378);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1
1
Gerull B et al. 2004 Nov (PMID:15489853); Syrris P et al. 2006 Jan 24 (PMID:16415378);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 4.52 3
Syrris P et al. 2006 Jan 24 (PMID:16415378);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.52    
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
2
Protein Interaction 0.5 0 - 2 1 1.5
Chen X et al. 2002 Mar 22 (PMID:11790773);
Expression 0.5 0 - 2 1 0.5
Mertens C et al. 1996 Nov (PMID:8922383);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Caspi O et al. 2013 Dec (PMID:24200905);
Non-patient cells 0.5 0 - 1 1 0.5
Hall C et al. 2009 (PMID:19533476);
Models Non-human model organism 2 0 - 4 4 2 3 3
Grossmann KS et al. 2004 Oct 11 (PMID:15479741); Cruz FM et al. 2015 Apr 14 (PMID:25857910);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
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
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
02/04/2020
EXPERT CURATION (DATE)
Definitive
03/08/2018
EVIDENCE SUMMARY
The relationship between PKP2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in PKP2 were first reported in humans with this disease as early as 2004 (Gerull et al., PMID: 15489853). PKP2 is the major causative gene for ARVC and accounts for 34%-74% of cases (McNAlly et al., 2005; PMID: 20301310). There are over 250 PKP2 variants listed in ClinVar for ARVC (missense, nonsense, frameshift, complex rearrangements, etc) (Novelli et al., 2018; PMID: 30619891). 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. This gene-disease relationship is supported by animal models, in vitro assays, and protein interactions. In summary, PKP2 is definitively associated with autosomal dominant ARVC. 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 Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October, 26, 2018 (SOP Version 6).