Submission Details

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.