ClinVar Genomic variation as it relates to human health

The c.449C>T;p.(Thr150Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 435829; PMID: 26588347; 24611737; 19244934; 18559663; 17590021; 17492953; 16507637) - PS4. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29311635) - PS3_supporting. The variant is present at low allele frequencies population databases (rs766665118 – gnomAD 0.00002628%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 24611737; 19244934) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.

The p.Thr150Ile variant in MC4R has been reported in at least 6 individuals with Obesity or who are overweight, segregated with disease in 2 obese relatives from 1 family (PMID: 16507637, 10903341, 17492953, 19244934, 26588347, 24611737), and has been identified in 0.04626% (16/34586) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766665118). 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 likely pathogenic and pathogenic in ClinVar (Variation ID: 435829). In vitro functional studies provide some evidence that the p.Thr150Ile variant may impact protein activity, ligand binding, and response to the ligand (PMID: 10903341, 16083993, 16752916, 16507637). 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. This variant is located in an important, well-established functional domain near the DRY motif. Variants in this position near the DRY motif are expected to impact receptor function in multiple receptor types (PMID: 16083993). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderate, PS4_Moderate, PM1 (Richards 2015).

This variant has been previously reported as a heterozygous change in multiple unrelated individuals with obesity and segregated with disease in two individuals from the same family (PMID: 10903341, 16507637, 17492953, 19244934, 24611737, 26588347). Functional studies demonstrate that it significantly reduces protein activity, ligand binding, and response to ligand (PMID: 10903341, 16083993, 16507637, 16752916). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0072% (18/251398) and thus is presumed to be rare. The c.449C>T (p.Thr150Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.449C>T (p.Thr150Ile) variant is classified as Likely Pathogenic.

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, 16752916, 17590021). 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. ClinVar contains an entry for this variant (Variation ID: 435829). This missense change has been observed in individual(s) with obesity (PMID: 10903341, 16507637, 18559663, 24611737, 26588347). This variant is present in population databases (rs766665118, gnomAD 0.05%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 150 of the MC4R protein (p.Thr150Ile).

Published functional studies demonstrate a damaging effect with a significant decrease in MC4R activity compared to wild-type (PMID: 31002796, 10903341); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16752916, 16083993, 31589614, 29311635, 24611737, 17628007, 18559663, 16507637, 19244934, 26588347, 31035493, 20406574, 17492953, 10903341, 31002796, 34561620, 33202557, 19301229, 17590021, 30926952)

The MC4R c.449C>T variant is predicted to result in the amino acid substitution p.Thr150Ile. This variant has been reported to be causative for autosomal dominant obesity (Albuquerque et al. 2014. PubMed ID: 24611737; Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Serra-Juhe et al. 2019. PubMed ID: 30926952). In vitro functional analyses indicate that the p.Thr150Ile variant results in partial loss of activity (Stutzmann et al. 2008. PubMed ID: 18559663; Vaisse et al. 2000. PubMed ID: 10903341; Lotta et al. 2019. PubMed ID: 31002796). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.