Gene Validity Curation

LMNA - arrhythmogenic right ventricular cardiomyopathy

Gene: LMNA (HGNC:6636)
Classification - 09/06/2019
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 first publication that associated LMNA variants with ARVC was published in 2012 and reported four patients without desmosomal variants that carried LMNA variants (22199124). These patients met 2010 TCC for ARVC and two had microscopic tissue evaluation confirming interstitial fibrosis and fatty replacement suggesting ARVC phenotype. One variant, p. Arg644Cys under 2015 ACMG criteria no longer is classified as a pathogenic variant. This study also included experimental evidence as immunohistochemistry staining of the biopsies did show delocalization of plakoglobin, which has been reported as pathologic for ARVC phenotype. Another study (25837155) in 2015 showed segregation in a large Italian family; however only the proband met ARVC TFC, the remaining 7 affected individuals only met borderline criteria for ARVC. Another study in 2016 (26620845) identified two LMNA variants in two probands. One only met borderline ARVC criteria with severe RV involvement and frequent PVCs. Experimental evidence was included as RV endomyocardial biopsy did demonstrate fibrous tissue replacement of the myocardium. LMNA mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and atrial arrhythmias.
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 1 1.5 1.5
Kato K et al. 2016 Oct (PMID:26620845);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
1.5
1.5
Quarta G et al. 2012 May (PMID:22199124); Kato K et al. 2016 Oct (PMID:26620845);
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 3.61 4
Quarta G et al. 2012 May (PMID:22199124); Kato K et al. 2016 Oct (PMID:26620845); Forleo C et al. 2015 Apr 2 (PMID:25837155);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.61    
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) 4
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 1
1
1
Quarta G et al. 2012 May (PMID:22199124);
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) 1

 


 

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 4 1 5 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
05/08/2020
EXPERT CURATION (DATE)
Limited
09/06/2019
EVIDENCE SUMMARY
The first publication that associated LMNA variants with ARVC was published in 2012 and reported four patients without desmosomal variants that carried LMNA variants (22199124). These patients met 2010 TCC for ARVC and two had microscopic tissue evaluation confirming interstitial fibrosis and fatty replacement suggesting ARVC phenotype. One variant, p. Arg644Cys under 2015 ACMG criteria no longer is classified as a pathogenic variant. This study also included experimental evidence as immunohistochemistry staining of the biopsies did show delocalization of plakoglobin, which has been reported as pathologic for ARVC phenotype. Another study (25837155) in 2015 showed segregation in a large Italian family; however only the proband met ARVC TFC, the remaining 7 affected individuals only met borderline criteria for ARVC. Another study in 2016 (26620845) identified two LMNA variants in two probands. One only met borderline ARVC criteria with severe RV involvement and frequent PVCs. Experimental evidence was included as RV endomyocardial biopsy did demonstrate fibrous tissue replacement of the myocardium. LMNA mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and atrial arrhythmias.