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).
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