Gene Validity Curation

CTNNA3 - arrhythmogenic right ventricular cardiomyopathy

Gene: CTNNA3 (HGNC:2511)
Classification - 08/06/2019
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: CTNNA3: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC: 2511 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy Three papers were reviewed related to CTNNA3 and ARVD (23136403, 21254927, 224213630). In one paper the CTNNA3 gene was analyzed in 76 ARVD probands that were negative for PKP2, DSP, DSG2, DSC2, and JUP. In one of the probands the heterozygous NM_013266.3(CTNNA3):c.281T>A p.(Val94Asp) variant was found. This variant was not observed in 245296 reference alleles from gnomAD and was not present in both healthy parents and brother suggesting that the variant occurred de novo. Unfortunately no information was given about paternity testing or family history for ARVD. Another proband showed the heterozygous variant NM_013266.3(CTNNA3):c.2296_2298del p.(Leu766del). This variant was not found in 30971 reference alleles from gnomAD but was inherited from her father that only showed a mild right ventricular dilation. Her ant inherited the variant as well but she was asymptomatic. Yeast two-hybrid studies with both variants showed some aberrations (23136403). In another paper a missense variant was found in one of 55 Danish ARVD patients. The variant was found 37 times in 276338 (1 times homozygous) reference alleles in gnomAD making it less likely as a causal variant. In addition the proband did carry a missense variant of unknown significance in DSP (21254927). Germline knockout of alphaT-catenin encoded by ctnna3 in the mouse alters PKP2 distribution without affecting other junctional components of the areae Compositae. These mutant mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC (224213630). Total genetic evidence points calculated = 1.5; Total experimental evidence points calculated = 2; Total awarded points = 3.5; Final classification = Limited.
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
1.5
1.5
van Hengel J et al. 2013 Jan (PMID:23136403);
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
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) 1.5
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 1 0.5
van Hengel J et al. 2013 Jan (PMID:23136403);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
van Hengel J et al. 2013 Jan (PMID:23136403);
Models Non-human model organism 2 0 - 4 4 1 1 1
Li J et al. 2012 Feb 15 (PMID:22421363);
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) 2

 


 

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 1.5 2 3.5 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
02/04/2020
EXPERT CURATION (DATE)
Limited
08/06/2019
EVIDENCE SUMMARY
CTNNA3: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC: 2511 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy Three papers were reviewed related to CTNNA3 and ARVD (23136403, 21254927, 224213630). In one paper the CTNNA3 gene was analyzed in 76 ARVD probands that were negative for PKP2, DSP, DSG2, DSC2, and JUP. In one of the probands the heterozygous NM_013266.3(CTNNA3):c.281T>A p.(Val94Asp) variant was found. This variant was not observed in 245296 reference alleles from gnomAD and was not present in both healthy parents and brother suggesting that the variant occurred de novo. Unfortunately no information was given about paternity testing or family history for ARVD. Another proband showed the heterozygous variant NM_013266.3(CTNNA3):c.2296_2298del p.(Leu766del). This variant was not found in 30971 reference alleles from gnomAD but was inherited from her father that only showed a mild right ventricular dilation. Her ant inherited the variant as well but she was asymptomatic. Yeast two-hybrid studies with both variants showed some aberrations (23136403). In another paper a missense variant was found in one of 55 Danish ARVD patients. The variant was found 37 times in 276338 (1 times homozygous) reference alleles in gnomAD making it less likely as a causal variant. In addition the proband did carry a missense variant of unknown significance in DSP (21254927). Germline knockout of alphaT-catenin encoded by ctnna3 in the mouse alters PKP2 distribution without affecting other junctional components of the areae Compositae. These mutant mice exhibit progressive dilated cardiomyopathy, gap junction remodelling, and increased sensitivity to ventricular arrhythmia following acute ischaemia, but not spontaneous ARVC (224213630). Total genetic evidence points calculated = 1.5; Total experimental evidence points calculated = 2; Total awarded points = 3.5; Final classification = Limited.