Submission Details

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).