ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.757G>A (p.Val253Ile) (rs187152753)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582762 SCV000692302 pathogenic Obesity 2014-03-04 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000582762 SCV001423084 uncertain significance Obesity 2020-01-29 no assertion criteria provided curation 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).

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