ClinVar Genomic variation as it relates to human health

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 76 of the MC4R protein (p.His76Arg). This variant is present in population databases (rs199558727, gnomAD 0.008%). This missense change has been observed in individual(s) with obesity (PMID: 24611737, 24705671, 30926952). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 18559663, 21729752, 23791567, 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.

Variant summary: MC4R c.227A>G (p.His76Arg) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251406 control chromosomes. c.227A>G has been reported in the literature in individuals affected with Obesity and it did not always segregate with disease (example, Stutzmann_2008, Albuquerque_2014, Berouwers_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Obesity. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of WT expression and reduced beta-arrestin recruitment at about 20-30% of WT (Berouwers_2021, Lotta_2019), however, this variant had no effect on the cAMP response (Stutzmann_2008). The following publications have been ascertained in the context of this evaluation (PMID: 24611737, 33761344, 31002796, 18559663). ClinVar contains an entry for this variant (Variation ID: 2078431). Based on the evidence outlined above, the variant was classified as VUS.

The MC4R c.227A>G variant is predicted to result in the amino acid substitution p.His76Arg. This variant has been reported in patients with an obesity phenotype (Stutzmann et al. 2008. PubMed ID: 18559663; Albuquerque et al. 2014. PubMed ID: 24611737; Moore et al. 2014. PubMed ID: 24705671; Serra-Juhé C et al 2019. PubMed ID: 30926952). One functional study reported no difference in protein activity when compared to wild type (Stutzmann et al. 2008. PubMed ID: 18559663), while others reported an impact on MC4R cell surface expression and basal signaling (Table 3, Wang and Tao. 2011. PubMed ID: 21729752; Lotta et al. 2019. PubMed ID: 31002796; Botha et al. 2023. PubMed ID: 37040537). The His76Arg substitution has also been found to exhibit reduced responsiveness to food intake-regulating hormones (Gillyard et al. 2019. PubMed ID: 31529534). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Although we suspect this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.