CAV3

Inheritance Pattern: AD

Disease ID:MONDO:0013686

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

CAV3 encodes Caveolin-3, a scaffolding protein present in cardiomyocyte caveolae and may be involved in ion channel regulation. Vatta et al. were the first, using a candidate-gene approach, to identify missense variants in CAV3, including putative de-novo variants (paternity not clearly confirmed), in patients with genotype-negative LQTS (PMID 17060380). Overall, however, there have been few studies published which support this gene-disease association and some of the variants in the literature are now known to be relatively frequent in populations, making them very unlikely to be a rare cause of rare disease. Furthermore, no segregation or case-control data is available. Accordingly, the Working Group classified the level of evidence for association of CAV3 with LQTS as limited. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”

Inheritance Pattern: AD

Disease ID:MONDO:0020704

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016146

Submitter: ClinGen

The relationship between *CAV3* and caveolinopathy, inherited in the autosomal dominant pattern, has been evaluated using the ClinGen Clinical Validity Framework as of July, 2022. This association was made using case-level, segregation, and experimental data. The *CAV3* gene is located on chromosome 3p25.3. The MANE SELECT transcript (NM_033337.3) is 1422 bp long with 2 exons encoding a 151-amino acid protein. More than 50 pathogenic and likely pathogenic variants reported in humans with clinical phenotypes that form the caveolinopathy spectrum are recorded in ClinVar, most of them being missense variants. Since the gene has only 2 exons, predicted loss of function variants are not expected to cause nonsense-mediated mRNA decay. Patients with caveolinopathy show variable clinical features including, but not limited to, proximal muscle weakness, exercise-induce muscle fatigue, increased serum creatine kinase levels, percussion-induced rapid rolling muscle contractions and hypertrophic cardiomyopathy (HCM). *CAV3* has been reported in association with caveoliopathy as early as 1998 (Minetti et al, PMID: 9537420, Betz et al, PMID: 11431690, McNally et al, PMID: 9536092). Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 6 publications (PMID: 9537420, 11431690, 19773168, 14672715, 26947586, 12082049). Variants in the gene segregated with disease in at least 7 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be dominant negative. Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, and protein interaction assays. *CAV3* encodes the caveolin 3 protein that functions as a scaffolding protein for organizing and concentrating certain caveolin-interacting molecules. Caveolin 3 is expressed specifically in the skeletal and cardiac muscle tissues ( PMID: 11259414, 9536092, 9537420). Caveolin 3 associates with the dystrophin-glycoprotein complex and changes in its expression lead to the disruption of the DGC and to downregulation of dystrophin protein levels (PMID: 9536092, 19584897). The CAV3 knock-out and the P105L transgenic mouse models sufficiently recapitulate the human caveolinopathy features, such as limb girdle weakness and hypertrophic cardiomyopathy. In summary, the *CAV3*-autosomal dominant caveolinopathy gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. OMIM entities: Familial hypertrophic cardiomyopathy; elevated serum creatine phosphokinase, long QT syndrome 9, Tateyama type distal myopathy, rippling muscle disease 2. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no significant difference in phenotype, inheritance pattern OR molecular mechanism in the above-mentioned disease entities. Therefore, all the entities have been lumped under caveolinopathy.

Inheritance Pattern: AD

Disease ID:MONDO:0012736

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019947

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0011910

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012736

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Genomics England PanelApp