CTNNA1

Inheritance Pattern: AD

Disease ID:MONDO:0020381

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012162

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012162

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0018630

Submitter: ClinGen

Inheritance Pattern: AD

Disease ID:MONDO:0012162

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100256

Submitter: ClinGen

*CTNNA1* gene encodes a member of the catenin family of proteins that is associated with both E-cadherin (encoded by CDH1 gene) and N-cadherin. The complexes play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. CTNNA1 was first reported in relation to autosomal dominant hereditary diffuse gastric cancer (HDGC) syndrome in 2013 (Majewski et al, PMID: 23208944). Similar to pathogenic variants of CDH1 gene, which are associated with lobular breast cancer (LBC) in addition to HDGC, we found that some patients with pathogenic CTNNA1 variants were also diagnosed with LBC. Additionally, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern and molecular mechanism; therefore, this curation has lumped HDGC and LBC as a disease term, CTNNA1-related diffuse gastric and lobular breast cancer syndrome. Please note, CTNNA1 is associated with patterned macular dystrophy 2 (MONDO:0012162), which was split from this curation due to phenotypic variability, and variant type differences. Fourteen variants (nonsense, splice site and frameshift) that have been reported in 16 probands (15 with diffuse gastric cancer and one with lobular breast cancer) described in 7 publications (PMIDs:23208944, 26182300, 29330337, 30515673, 29025585, 32051609 and 36038258) are included in this curation. The mechanism of pathogenicity is reported as heterozygous loss of function (LOF). In a large cohort of 151,425 individuals with personal/family history of cancer (Clark et al, 2020 PMID: 32051609) LOF variants in this gene were also identified in unaffected individuals and individuals with other cancer types suggesting the spectrum of cancers may change over time. This gene-disease relationship is also supported by experimental evidence (protein interactions, cellular and animal models, expression studies) (PMIDs:2788574, 9023354, 11239416, 12080224, 29774524 and 22080244). Experimental evidence shows that CTNNA1 is a protein involved in the adherens junctions (AJ) that binds cadherin/β-catenin to actin cytoskeleton, promoting cell adhesion. In summary, there is definitive evidence to support the relationship between CTNNA1 and autosomal dominant hereditary diffuse gastric cancer and lobular breast cancer. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was curated on 02/23/2023 by the Hereditary Cancer GCEP (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0020242

Submitter: ClinGen

*CTNNA1* was first reported in association with autosomal dominant maculopathy in 2016 (Saksens et al., PMID: 26691986). The retinal phenotype is characterized by adult-onset patterned pigmentary changes involving the macula and retinal pigment epithelium, initially described as butterfly-shaped pattern dystrophy. The disease is generally slowly progressive, although macular atrophy and choroidal neovascularization have also been reported. The *CTNAA1*-related maculopathy phenotype was previously split from *CTNNA1*-related cancer predisposition by the Hereditary Cancer GCEP. The two conditions show distinct phenotypes and variant spectra: cancer is predominantly associated with loss-of-function variants, whereas the retinal phenotype is associated with heterozygous missense variants. No families with both phenotypes have been reported Seven unique missense variants have been reported in individuals with *CTNNA1*-related maculopathy (p.Glu307Lys, p.Leu318Ser, p.Ser322Leu, p.Thr325Ala, p.Ile431Met, p.Glu432Lys, and p.Ser439Phe, PMIDs: 26691986, 33137351, 38573304, 40455352). Several of these variants cluster within two regions of α-catenin, involving residues Leu318–Thr325 and Ile431–Glu432. The recurrent p.Leu318Ser variant segregated with the retinal phenotype in two families, with a combined estimated LOD score of 3.0. The disease mechanism is not fully established. The reported missense variants cluster in regions of α-catenin involved in mechanosensing and adherens junction regulation. Experimental evidence includes *CTNNA1* expression in human retinal pigment epithelium, functional alteration in non-patient cells, and a *Ctnna1* mouse model (PMIDs: 23487591, 39786338, 26691986). The mouse model carries the missense variant p.Leu436Pro, which has not been reported in humans but is located close to disease-associated human variants. Heterozygous mice showed progressive retinal pigment mottling and structural and functional RPE abnormalities. *Ctnna1* knockout models were not scored, as loss of function does not appear to be the disease mechanism and these models mainly showed developmental eye abnormalities that did not closely resemble the human phenotype. *CTNNA1* variants have also been reported in familial exudative vitreoretinopathy (FEVR) (PMID: 33497368). This evidence was not included because the phenotype and proposed mechanism differ from *CTNNA1*-related patterned maculopathy and may represent a separate gene-disease relationship. In summary, *CTNNA1* has a Definitive association with *CTNAA1*-related maculopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on September 3rd, 2026 (SOP Version 12).