Descriptive analysis of MC4R gene variants associated with obesity listed on ClinVar.

Objectives: The most recent version of ClinVar was utilized to filter variants of the MC4R gene based on location, condition, and clinical significance with the goal of obtaining benign and disease-associated variants of the MC4R gene. MC4R gene variants can lead to dysregulation of energy expenditure and appetite control, which prompted this study to delineate the distinctive features of MC4R gene variants submitted to the ClinVar repository regarding their association with obesity and related phenotypes.

Method: A thorough search was conducted in the ClinVar repository for clinically significant MC4R variants through the utilization of the gene name MC4R[gene] and MeSH terms "MC4R[gene]" and "single gene"[properties]" in the search box. Leading to the identification of clinically significant genetic variants associated with obesity.

Results: Utilizing the ClinVar clinical significance ranking system, the MC4R variants were categorized into six groups based on ClinVar/ClinGen's ranking system: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), benign (B), likely benign (LB), and conflicting classifications (CC). A total of 103 pathogenic variants were observed. These variants have different clinical significance that are associated with monogenic obesity, monogenic diabetes, and body mass index quantitative traits. It was observed that over 80% of the mutations were single nucleotide variants, with nearly half being missense mutations spread throughout the topological and transmembrane domains. Furthermore, TM7 had the highest number of single nucleotide missense mutations.

Conclusion: Further analysis of the relationships between monogenic obesity and diabetes requires additional investigation to discover the underlying causes of these conditions. The study findings imply that mutations in MC4R's topological and transmembrane regions may significantly influence receptor activation and signaling. As more MC4R variants are discovered and their correlation with obesity is established, there is potential to definitively establish a strong connection between MC4R pathogenic variants and the development of obesity.