CTNNA3

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0005453

Submitter: ClinGen

*CTNNA3* was first reported in relation to congenital heart disease in 2013 (Symou et al., PMID:23481551). Five probands with multi-gene CNVs (4 gross deletions, 1 duplication) at the 10q21.3 location have been reported in four publications (PMIDs: 23481551, 24297458, 28378413, 28472932). Although this gene-disease relationship is supported by a protein interaction study (PMID:​ 15302915), no reports have directly implicated the gene in humans. In summary, the evidence supporting the relationship between *CTNNA3* and congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *CTNNA3* plays in this disease. This gene-disease pair was originally evaluated by the ClinGen Congenital Heart Disease GCEP on October 17th, 2023 (SOP Version 9). It was reevaluated on August 10th, 2026 (SOP Version 12). As a result of this reevaluation, no new evidence was reviewed and the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0000908

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0000908

Submitter: Ambry Genetics