Gene Validity Curation

DSC2 - familial isolated arrhythmogenic right ventricular dysplasia

Gene: DSC2 (HGNC:3036)
Classification - 09/14/2018
Disease: familial isolated arrhythmogenic right ventricular dysplasia (MONDO_0016342)
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 DSC2 and arrhythmogenic right ventricular dysplasia (autosomal dominant) and arrhythmogenic right ventricular dysplasia with mild palmoplantar keratoderma with or without woolly hair (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of July, 2018. Variants in DSC2 were first reported in humans with this disease as early as 2006 (Syrris et al., PMID: 17033975). At least 13 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 8.5 points. Variants in this gene have been reported in at least 13 probands in 6 publications (PMIDs: 17963498, 21062920, 23863954, 17186466, 18957847, 17033975). This gene-disease relationship is supported by animal models, expression studies, and protein interactions. In summary, DSC2 is definitively associated with ARVD (AD) and ARVD with mild palmoplantar keratoderma with or without woolly hair (AR). 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
Proband with predicted or proven null variant 1.5 0-2 10 9 7 7
Syrris P et al. 2006 Nov (PMID:17033975); Heuser A et al. 2006 Dec (PMID:17186466); Gerull B et al. 2013 Aug (PMID:23863954); Gehmlich K et al. 2011 Apr 01 (PMID:21062920); Simpson MA et al. 2008 Oct 29 (PMID:18957847);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
1.5
1.5
Beffagna G et al. 2007 Oct 26 (PMID:17963498); Gehmlich K et al. 2011 Apr 01 (PMID:21062920);
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) 8.5
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
Gehmlich K et al. 2011 Apr 01 (PMID:21062920);
Expression 0.5 0 - 2 2 1
De Bortoli M et al. 2010 Jul (PMID:20197793); Lorimer JE et al. 1994 Oct-Dec (PMID:7711832);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1.5 3.5
Brodehl A et al. 2017 Mar 24 (PMID:28339476);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Heuser A et al. 2006 Dec (PMID:17186466);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 8.5 5.5 14 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 DSC2 and arrhythmogenic right ventricular dysplasia (autosomal dominant) and arrhythmogenic right ventricular dysplasia with mild palmoplantar keratoderma with or without woolly hair (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of July, 2018. Variants in DSC2 were first reported in humans with this disease as early as 2006 (Syrris et al., PMID: 17033975). At least 13 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 8.5 points. Variants in this gene have been reported in at least 13 probands in 6 publications (PMIDs: 17963498, 21062920, 23863954, 17186466, 18957847, 17033975). This gene-disease relationship is supported by animal models, expression studies, and protein interactions. In summary, DSC2 is definitively associated with ARVD (AD) and ARVD with mild palmoplantar keratoderma with or without woolly hair (AR). 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).