ClinVar Genomic variation as it relates to human health

The p.Val253Ile variant in MC4R has been reported in 7 individuals (including 1 Austrian, 1 German, and 1 European individuals) with Obesity (PMID: 10903343, 17286227, 16492696, 18559663, 24705671, 12646665), and 1 Spanish individual without Obesity (PMID: 12629567), and has been identified in 0.01129% (4/35436) of Latino chromosomes, 0.009799% (3/30614) of South Asian chromosomes, and 0.007748% (10/129070) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs187152753). This variant did not cosegregate with Obesity in a parent and child with disease (PMID: 17286227). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 492862). In vitro functional studies provide some evidence that the p.Val253Ile variant may slightly impact the response to receptor activation, cAMP generation (PMID: 12588803, 12646665), but may not impact ligand binding or cell surface expression (PMID: 12499395, 16752916, 24705671). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS3_Supporting (Richards 2015).

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 253 of the MC4R protein (p.Val253Ile). This variant is present in population databases (rs187152753, gnomAD 0.02%). This missense change has been observed in individual(s) with obesity (PMID: 10903343, 29970488, 30811542). ClinVar contains an entry for this variant (Variation ID: 492862). 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 not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 12499395, 12588803, 12646665, 12690102, 16752916, 18559663, 31002796). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The MC4R c.757G>A variant is predicted to result in the amino acid substitution p.Val253Ile. This variant has been reported in several individuals with obesity (Farooqi et al. 2000. PubMed ID: 10903343; Stutzmann et al. 2008. PubMed ID: 18559663; Patient 26, Kleinendorst et al. 2018. PubMed ID: 29970488). However, functional studies suggest that this variant does not significantly impair receptor expression or activation (Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Nijenhuis et al. 2003. PubMed ID: 12690102; Xiang et al. 2006. PubMed ID: 16752916). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.