Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV004018393 | SCV004848239 | pathogenic | Obesity due to melanocortin 4 receptor deficiency | 2018-09-19 | criteria provided, single submitter | clinical testing | The p.Ser116PhefsX6 variant in MC4R has been reported in 2 homozygous individuals with severe early-onset obesity and segregated with disease in at least 3 heterozygous relatives from 2 families (Dubern 2007, Tunç 2017). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 116 and leads to a premature termination codon 6 amino acids downstream. 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 five transmembrane domains 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). 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 obesity due to Melanocortin 4 Receptor Deficiency in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting, PM1, PP1. |