Submission Details

BVES (Blood Vessel Epicardial Substance) a.k.a POPDC1 (Popeye Domain-Containing 1) is one of the genes of the Popeye Domain in addition to POPDC2 and POPDC3. It is an evolutionarily conserved membrane protein with a molecular function in the establishment and/or maintenance of cell integrity. It is expressed in the cardiac and the skeletal muscle and plays an important role in the development and the maintenance of these tissues. POPDC1BVES is associated with autosomal recessive limb-girdle muscular dystrophy (type 2X included), where the main clinical features are slowly progressive proximal muscle weakness in lower limbs, usually associated with cardiac disturbances including arrhythmia. BVES was first reported in relation to autosomal recessive limb-girdle muscular dystrophy type 2X by Schindler et al. in 2016 (PMID: 26642364), who provided one of the most complete clinical and molecular descriptions with functional studies. More than 70 variants have been identified in BVES POPDC1 but only around 49 with clinical significance are assumed to cause LGMD2X. ClinVar reports at least 10 pathogenic/likely pathogenic variants in BVES. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 7 probands in 5 publications (PMID: 26642364, 31119192, 33310206, 35660068, 35718670). Variants in this gene segregated with disease in 3 additional family members. The mechanism for disease is biallelic loss of function. Functional studies showed that mutant variants lead to important reduction of POPDC1 protein in cAMP affinity in skeletal muscle from patients in addition to impaired membrane trafficking. A certain clinical variability was noted, within the same family and among unrelated individuals. This variability relates to the age of onset of the disease within the same family (PMID:26642364, PMID:31119192), the severity of the phenotype and the progression of the disease (PMID:33310206). Individuals with nonsense variants leading to premature truncation of the protein product appear to display a more severe phenotype (PMID: 33310206). Summary of experimental data (2 points): This gene-disease relationship is supported by limited experimental evidence. Expression studies showed that POPDC1 is prominently expressed in the sarcolemma in healthy muscle fibers, while in affected muscles, a significant reduction in membrane localization of both POPDC1 and POPDC2 was observed (PMID: 10882522, 27347491, 31119192). In summary, BVES is definitively associated with autosomal recessive limb-girdle muscular dystrophy type 2X. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.