ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.806T>A (p.Ile269Asn)

gnomAD frequency: 0.00011  dbSNP: rs79783591
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000499660 SCV000052816 uncertain significance not specified 2019-01-25 criteria provided, single submitter clinical testing Variant summary: MC4R c.806T>A (p.Ile269Asn) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 277298 control chromosomes, predominantly at a frequency of 0.0073 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in MC4R causing Early Onset Obesity phenotype (0.0005), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, c.806T>A has been reported in the literature in multiple individuals affected with Early Onset Obesity (Hohenadel_2014, Tan_2009). Furthermore, at-least two of these reports identified this variant in individuals of Hispanic/Latina ancestry who are enriched for this variant among the control cohorts. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Obesity. Experimental evidence evaluating an impact on protein function demonstrated the variant to have a significantly different EC50 (the concentration of ligand needed to achieve 50% of maximum effect) than that of the wild type (WT) receptor (Thearle_2012, Calton_2009), reduced expression at the cell surface and decreased receptor binding (Hohenadel_2014, Tan_2009) while, it also exhibited defective ligand-stimulated response compared to WT and was determined to have biased signaling in the ERK1/2 pathway (He_2014). Studies were contradictory in terms of cyclic AMP response after agonist administration either detecting loss of function or no significant difference in function compared to WT (Hohenadel_2014, Tan_2009). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the possibility that this is likely to represent a benign variation cannot be excluded. Due to equivocal reports of functional relevance the variant was classified as uncertain significance.
Genetic Services Laboratory,University of Chicago RCV000499660 SCV000595716 uncertain significance not specified 2017-03-14 criteria provided, single submitter clinical testing
Invitae RCV000906648 SCV001051300 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000030158 SCV001423113 uncertain significance Obesity 2020-01-22 criteria provided, single submitter curation The p.Ile269Asn variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 19091795), and has been identified in 0.7309% (259/35438) of Latino chromosomes, including 5 homozygotes, by the Genome Aggregation Database (gnomAD,; dbSNP rs79783591). 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 as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 36486). In vitro functional studies provide some evidence that the p.Ile269Asn variant may impact cell surface expression, protein folding, and receptor activation (PMID: 18801902, 19091795). 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: PS3, PS4_Supporting (Richards 2015).
Athena Diagnostics Inc RCV000906648 SCV001476539 pathogenic not provided 2020-10-07 criteria provided, single submitter clinical testing Although the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, this variant was shown to associate with obesity in Mexican children and adults (PMID:31841602, Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments showed reduced cell surface expression and ligand binding, as well as loss of signal transduction (PMID:18801902,24276017,31002796). Computational tools predict that this variant is damaging.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000030158 SCV000692303 pathogenic Obesity 2014-05-23 no assertion criteria provided clinical testing

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