ClinVar

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MC4R function (PMID: 10903341, 12690102, 16507637, 16752916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 1284736). This missense change has been observed in individual(s) with clinical feartures autosomal dominant obesity due to melanocortin 4 receptor deficiency (PMID: 10199800, 10903341, 29970488, 30991789, 32185475). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs13447332, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 165 of the MC4R protein (p.Arg165Trp).