ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.161T>C (p.Leu54Pro) (rs376439188)

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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 RCV000582060 SCV000692296 pathogenic Obesity 2017-05-04 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000582060 SCV001423085 uncertain significance Obesity 2020-01-22 no assertion criteria provided curation The p.Leu54Pro variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 29758564), and has been identified in 0.0008801% (1/113626) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376439188). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. 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: 492861). In vitro functional studies provide some evidence that the p.Leu54Pro variant may slightly impact protein function (PMID: 18801902). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PP3, PS4_Supporting (Richards 2015).

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