Gene Validity Curation

LDB3 - arrhythmogenic right ventricular cardiomyopathy

Gene: LDB3 (HGNC:15710)
Classification - 09/12/2019
Disease: arrhythmogenic right ventricular cardiomyopathy (MONDO_0016587)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy EP
Evidence Summary: The association of LDB3 with ARVC is disputed. A study (25041374) investigated a family affected by ARVC on which Sanger sequencing failed to find a disease‐causing mutation in any of the five desmosomal genes in the proband (DSP, JUP, DSC2, DSG2, PKP2). The authors performed Next Generation Sequencing by using a 134 genes panel in order to discover a candidate disease‐causing gene. Genetic screening identified a missense variant on LDB3 causing the aminoacid substitution Thr351Ala, this variant was reported in ClinVar as conflicting interpretation (VUS, LB). This variant shows a high MAF in the general population to be associated with the disease even though the proband and family carriers do have ARVC. There is disputed evidence that the identified LDB3 variant contribute to the ARVC phenotype and there is no known disease mechanism that would link LDB3 with ARVC.
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 1
0.1
0.1
Lopez-Ayala JM et al. 2015 Aug (PMID:25041374);
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) 0.1
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 0

 


 

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 0.1 0 0.1 NO
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)
Limited
02/04/2020
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
02/04/2020
REASON(S) FOR CHANGE
Only a single variant was found, and the MAF of that variant was above the ARVC EP cut-off.
EXPERT CURATION (DATE)
Disputed
09/12/2019
EVIDENCE SUMMARY
The association of LDB3 with ARVC is disputed. A study (25041374) investigated a family affected by ARVC on which Sanger sequencing failed to find a disease‐causing mutation in any of the five desmosomal genes in the proband (DSP, JUP, DSC2, DSG2, PKP2). The authors performed Next Generation Sequencing by using a 134 genes panel in order to discover a candidate disease‐causing gene. Genetic screening identified a missense variant on LDB3 causing the aminoacid substitution Thr351Ala, this variant was reported in ClinVar as conflicting interpretation (VUS, LB). This variant shows a high MAF in the general population to be associated with the disease even though the proband and family carriers do have ARVC. There is disputed evidence that the identified LDB3 variant contribute to the ARVC phenotype and there is no known disease mechanism that would link LDB3 with ARVC.