Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV004018395 | SCV004848241 | likely pathogenic | Obesity due to melanocortin 4 receptor deficiency | 2018-09-19 | criteria provided, single submitter | clinical testing | The p.Arg236AlafsX6 variant in MC4R has not been previously reported in individuals with obesity, but has been identified in 1/111542 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 236 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 two 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, although additional studies are required to fully establish its clinical significance, the p.Arg236AlafsX6 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM1. |