Gene Validity Curation

JUP - arrhythmogenic right ventricular cardiomyopathy

Gene: JUP (HGNC:6207)
Classification - 07/27/2018
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
Evidence Summary: Twenty-one papers were reviewed related to JUP and ARVC (2945574, 21668431, 2945574, 9610536, 18937352, 10902626, 15851108, 27170944, 11691526, 16893920, 29802319, 31275992, 25820315, 25820315, 25765472, 25705887, 25087486, 21668431, 20130592, 17924338, 20031617). The initial discovery of a homozygous two-nucleotide deletion (c.2038_2039delTG; p.Trp680Gly_fs) in JUP underlying Naxos disease, which includes ARVC with palmoplantar keratoderma and woolly hair, led to further focus on this and other desmosome genes in non-syndromic ARVC (McCoy et al, PMID 10902626). Murine models support the functional, arrhythmic, and histopathologic cardiac effects from loss-of-function variants in Jup (PMID 27170944; 25705887). Heterozygous pathogenic variants in JUP account for a low percentage of non-syndromic ARVC (0.5%; PMID 25820315). Despite the relatively low percentage, null and missense variants have evidence of impact in multiple families with ARVC. This leads to strong genetic evidence for the role of pathogenic variants in JUP for dominant, non-syndromic ARVC (score 10.5). The experimental evidence supports this association (score 5.5), with final classification: Strong.
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 13.5 10
McKoy G et al. 2000 Jun 17 (PMID:10902626);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Asimaki A et al. 2007 Nov (PMID:17924338);
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 0 0  
Candidate gene sequencing 0.6 2
McKoy G et al. 2000 Jun 17 (PMID:10902626);
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) 10.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Kaplan SR et al. 2004 May (PMID:15851108);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Kaplan SR et al. 2004 May (PMID:15851108);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Zhang Z et al. 2015 Apr (PMID:25705887);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Zhang Z et al. 2015 Apr (PMID:25705887);
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 10.5 5.5 16 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
05/13/2020
EXPERT CURATION (DATE)
Definitive
07/27/2018
EVIDENCE SUMMARY
Twenty-one papers were reviewed related to JUP and ARVC (2945574, 21668431, 2945574, 9610536, 18937352, 10902626, 15851108, 27170944, 11691526, 16893920, 29802319, 31275992, 25820315, 25820315, 25765472, 25705887, 25087486, 21668431, 20130592, 17924338, 20031617). The initial discovery of a homozygous two-nucleotide deletion (c.2038_2039delTG; p.Trp680Gly_fs) in JUP underlying Naxos disease, which includes ARVC with palmoplantar keratoderma and woolly hair, led to further focus on this and other desmosome genes in non-syndromic ARVC (McCoy et al, PMID 10902626). Murine models support the functional, arrhythmic, and histopathologic cardiac effects from loss-of-function variants in Jup (PMID 27170944; 25705887). Heterozygous pathogenic variants in JUP account for a low percentage of non-syndromic ARVC (0.5%; PMID 25820315). Despite the relatively low percentage, null and missense variants have evidence of impact in multiple families with ARVC. This leads to strong genetic evidence for the role of pathogenic variants in JUP for dominant, non-syndromic ARVC (score 10.5). The experimental evidence supports this association (score 5.5), with final classification: Strong.