CAV1

Inheritance Pattern: AD

Disease ID:MONDO:0012923

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

*CAV1* was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2012 (Austin ED et al., PMID: 22474227). Pulmonary Arterial Hypertension is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. As the genetic variants associated with lipodystrophies are different from those associated with H/IPAH ((with the exception of one reported case of a heterozygous C-terminal frameshift variant, c.479_480del; p.(Phe160Ter), identified in an individual with PAH and severe neonatal progeroid lipodystrophy syndrome (PMIDs: 26176221 and 25898808)), and the molecular mechanisms are likely to be different, *CAV1* was curated independently by both the PH GCEP and the monogenic diabetes GCEP, and both curations are available on the ClinGen website. Summary of Genetic Evidence: Three frameshift and five missense variants have been found in nine probands across five publications (PMIDs: 22474227, 29631995, 30578383, 31727138, 33007923). The mechanism of pathogenicity seems to be dominant negative. Summary of Experimental Evidence: This gene-disease association is also supported by biochemical function, functional alteration in patient cells, animal models and non-human model rescue studies (PMIDs: 16537870, 28904206, 28468941, 12177436, 17893196). CAV1 is expressed in lung endothelial and smooth muscle cells, and expression is decreased or absent in plexiform lesions. Investigation of patient fibroblasts expressing a *CAV1* c.474delA variant demonstrated reduced caveolae density and caveolar protein levels, and expression of the mutant protein caused reduced wild-type protein. These data are consistent with a dominant negative mechanism of disease. Further, the increased SMAD1/5/8 phosphorylation observed in *CAV1* patient fibroblasts was not rescued by transduction with wild-type *CAV1*, arguing against haploinsufficiency as the pathogenetic mechanism. Finally, *CAV1* knockout mice, but interestingly not patients with homozygous null variants (PMIDs: 34643546 and 18211975), exhibit pulmonary vascular remodeling and features consistent with PAH, including higher pulmonary artery pressure, greater pulmonary vascular resistance, enhanced basal vascular permeability and RV hypertrophy; and the phenotype is largely rescued by endothelial re-expression of *CAV1*. In summary, *CAV1* is definitively associated with autosomal dominant pulmonary arterial hypertension. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The PH GCEP approved this classification on 8/30/2022 (SOP v9.0). Administrative edits and additional citations were added on 7/30/2025.

Inheritance Pattern: AD

Disease ID:MONDO:0017148

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0006573

Submitter: ClinGen

Heterozygous variants in the Caveolin-1 (CAV1) gene were first reported in association with autosomal dominant lipodystrophy in 2008 (Cao et al., PMID: 18237401). So far, only two variants (a frameshift and a 5’UTR variant) have been reported in association with atypical partial lipodystrophy, severe type 5 hyperlipoproteinemia, recurrent pancreatitis, and, in some affected individuals, congenital cataracts and neurological involvement (PMID: 18237401). Evidence supporting this gene-disease relationship includes limited case-level data, with no segregation data or experimental data available. Variants in this gene have been reported in at least two probands in a single publication (PMID: 18237401), and the genetic evidence has reached a total of only 1.60 points. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism and phenotypic variability for variants causing CAV1-related lipodystrophy (CGL3 vs familial partial and/or progeroid lipodystrophy) and pulmonary arterial hypertension. Therefore, we curated *CAV1* as a split curation for autosomal dominant familial partial and/or progeriod lipodystrophy (OMIM:606721). Autosomal recessive congenital, generalized lipodystrophy (OMIM:612526) and autosomal dominant pulmonary arterial hypertension (OMIM:615343) were curated separately in split curations. In summary, there is limited evidence supporting the relationship between CAV1 and autosomal dominant familial partial lipodystrophy. Additional studies are needed to further establish this gene-disease association; the total score of 1.60 falls within the "limited" range. The lack of genetic evidence outside a single publication remains a major limitation. The MDEP GCEP approved this classification on 6/30/2025 (SOP v11.0).

Inheritance Pattern: AR

Disease ID:MONDO:0012923

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014135

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011714

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014135

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

Variants in the CAV1 gene have been reported in relation to autosomal dominant pulmonary hypertension and congenital lipodystrophy along with autosomal recessive familial lipodystrophy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability for these assertions. Therefore, these assertions have been split into the following disease entities: autosomal dominant Amyotrophic lateral Sclerosis (ALS), Pulmonary Hypertension (PPH3), Congenital Lipodystrophy (CGL3) and Familial Lipodystrophy – Type 7 (FPLD7). This curation for autosomal dominant ALS does not include probands from the other reported diseases. Heterozygous missense variants in coding and enhancer regions of the CAV1 gene have been reported till date in individuals with ALS (PMIDs: 33264630). In all instances of literature when available, affected probands with CAV1 coding and CAV1/CAV2 enhancer variants are identified to have dysregulation caveolar protein expression levels (PMIDs: 33264630, 36937187, 30894019). The maximum score for genetic evidence through aggregate variant analysis is 5 (Limited 0-6). Evidence supporting this gene disease pair also includes experimental data from patient lymphoblastoid cells and iPSC derived neurons showing expression of the calveolar protein (33264630, 36937187).

Inheritance Pattern: AR

Disease ID:MONDO:0012923

Submitter: ClinGen

Human pathogenic *CAV1* variants were first reported in 2008 in association with autosomal recessive congenital generalized lipodystrophy type 3 (CGL3) (Kim et al., PMID: 18541701). We have curated the inheritance pattern for *CAV1*-related congenital generalized lipodystrophy as autosomal recessive, because a recessive mode of inheritance has been reported since (Kim et al., PMIDs: 18541701; Karhan et al., PMID: 34643546). Homozygous variants, including nonsense and frameshift mutations have been reported. Typical autosomal recessive cases due to homozygous *CAV1* variants present with a near-total absence of both subcutaneous and visceral adipose tissue, severe insulin resistance, hypertriglyceridemia, hepatomegaly, hyperinsulinemia, muscular hypertrophy, and diabetes mellitus, even in early infancy (Kim et al., PMIDs: 18541701; Karhan et al., PMID: 34643546). To date, only two homozygous *CAV1* variants (one nonsense and one frameshift) have been reported to cause congenital generalized lipodystrophy type 3 in humans. Evidence supporting the association of *CAV1* with CGL3 includes case-level data and experimental data. The aggregated score for case-level data is 7 points. Variants in this gene were curated for this summary in 5 patients in 2 families in 2 publications (PMIDs: 18541701, 34643546) presenting as congenital, generalized lipodystrophy type 3. The calculated LOD score was 2.81. The total score for genetic evidence was 7 points. This gene-disease relationship is supported by functional assays and knockout mouse models (PMIDs: 18541701, 34643546,11739396,12660144). Total points for the experimental evidence are 6. Total points for genetic and experimental evidence together are 13. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism and phenotypic variability for variants causing CAV1 related lipodystrophy (CGL3 vs familial partial and/or progeroid lipodystrophy) and pulmonary arterial hypertension. Therefore, we curated *CAV1* as a split curation for autosomal recessive congenital, generalized lipodystrophy (OMIM:612526). Autosomal dominant familial partial and/or progeriod lipodystrophy(OMIM:606721) and autosomal dominant pulmonary arterial hypertension (OMIM:615343) have or will be curated separately in split curations. In summary, *CAV1* is definitively associated with autosomal recessive, congenital generalized lipodystrophy type 3 from birth or early infancy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Approved by the Monogenic Diabetes GCEP May 14, 2025 (SOP v11).