ClinVar

Description

The p.Tyr287X variant in MC4R has been reported in at least 1 homozygous individual with obesity and segregated with disease in 2 heterozygous relatives (Farooqi 2003, Yeo 2003). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 287. The MC4R protein is encoded by a single exon; therefore, this alteration is more likely to escape nonsense mediated decay (NMD), resulting in a truncated protein that is missing one transmembrane domain and the c-terminal tail. The c-terminal tail contains a peptide signal which is required for targeting the MC4R protein to the plasma membrane, and removal of that peptide results in cytoplasmic retention of the MC4R protein (Ho 1999). In addition, in vitro studies found this variant resulted in a complete loss of protein activity and absent or reduced cell surface expression (Farooqi 2003, Yeo 2003, Xiang 2003). Haploinsufficiency of the MC4R gene is an established disease mechanism in MC4R-related obesity. In summary, this variant meets criteria to be classified as pathogenic for MC4R-related obesity in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM1, PS3_Supporting, PM3_Supporting.