ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.449C>T (p.Thr150Ile) (rs766665118)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503229 SCV000595718 likely pathogenic Obesity, autosomal dominant 2016-10-18 criteria provided, single submitter clinical testing
Invitae RCV001378257 SCV001575791 likely pathogenic not provided 2017-11-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 150 of the MC4R protein (p.Thr150Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs766665118, ExAC 0.03%). This variant has been reported in several individuals affected with morbid obesity (PMID: 24611737, 16507637, 10903341, 26588347, 18559663). ClinVar contains an entry for this variant (Variation ID: 435829). Experimental studies have shown that this missense change leads to a reduction in receptor activation in vitro and decreased potency for the endogenous melanocortin agonists examined (PMID: 10903341, 16752916, 17590021). 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582643 SCV000692299 pathogenic Obesity 2014-05-13 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000582643 SCV001423115 likely pathogenic Obesity 2020-01-22 no assertion criteria provided curation 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).

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