ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs766665118
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Total submissions: 5
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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
Broad Institute Rare Disease Group, Broad Institute RCV000582643 SCV001423115 likely pathogenic Obesity 2020-01-22 criteria provided, single submitter 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).
Invitae RCV001378257 SCV001575791 likely pathogenic not provided 2021-08-31 criteria provided, single submitter clinical testing
DASA RCV000582643 SCV002073756 likely pathogenic Obesity 2022-02-05 criteria provided, single submitter clinical testing 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582643 SCV000692299 pathogenic Obesity 2014-05-13 no assertion criteria provided clinical testing

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