Gene Validity Curation

DSG2 - arrhythmogenic right ventricular cardiomyopathy

Gene: DSG2 (HGNC:3049)
Classification - 09/14/2018
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 EP Contributors:
  • UNC Biocuration Core
Evidence Summary: The relationship between DSG2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of July, 2018. Variants in DSG2 were first reported in humans with this disease as early as 2006 (Pilchou et al., PMID: 16505173). Variation in DSG2 is a well-known cause of ARVC and accounts for 5%-26% of cases (McNAlly et al., 2005; PMID: 20301310). Since this gene-disease relationship is well-known, there is a significant amount of case-level data, segregation data and experimental data 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, expression assays, and protein interactions. In summary, DSG2 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 September 14, 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 1
2
2
Gandjbakhch E et al. 2009 Mar (PMID:19151369);
Proband with predicted or proven null variant 1.5 0-2 10 6 8 8
Pilichou K et al. 2006 Mar 07 (PMID:16505173); Awad MM et al. 2006 Jul (PMID:16773573); Syrris P et al. 2007 Mar (PMID:17105751);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 10
2.3
2.3
Pilichou K et al. 2006 Mar 07 (PMID:16505173); Awad MM et al. 2006 Jul (PMID:16773573); Rasmussen TB et al. 2013 May (PMID:23381804);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
1
2
Harmon RM et al. 2013 Dec (PMID:24205984);
Protein Interaction 0.5 0 - 2 1 0.5
Chen X et al. 2002 Mar 22 (PMID:11790773);
Expression 0.5 0 - 2 1 0.5
Schäfer S et al. 1994 Apr (PMID:8143788);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4 4
Rizzo S et al. 2012 Sep 01 (PMID:22764152); Pilichou K et al. 2009 Aug 03 (PMID:19635863); Kant S et al. 2015 Aug (PMID:26085008);
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
08/06/2019
EXPERT CURATION (DATE)
Definitive
09/14/2018
EVIDENCE SUMMARY
The relationship between DSG2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of July, 2018. Variants in DSG2 were first reported in humans with this disease as early as 2006 (Pilchou et al., PMID: 16505173). Variation in DSG2 is a well-known cause of ARVC and accounts for 5%-26% of cases (McNAlly et al., 2005; PMID: 20301310). Since this gene-disease relationship is well-known, there is a significant amount of case-level data, segregation data and experimental data 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, expression assays, and protein interactions. In summary, DSG2 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 September 14, 2018 (SOP Version 6).