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).
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