ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.523G>A (p.Ala175Thr)

gnomAD frequency: 0.00031  dbSNP: rs121913563
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000015406 SCV001287368 uncertain significance Obesity 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mendelics RCV002247343 SCV002518222 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000768579 SCV002815558 uncertain significance BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 2022-05-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002513063 SCV003472347 benign not provided 2023-09-19 criteria provided, single submitter clinical testing
New York Genome Center RCV000768579 SCV003925282 uncertain significance BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 2022-03-15 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV002513063 SCV005193387 uncertain significance not provided criteria provided, single submitter not provided
OMIM RCV000768579 SCV000035667 pathogenic BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 2003-03-20 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000015406 SCV000692300 pathogenic Obesity 2011-03-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003415708 SCV004116071 uncertain significance MC4R-related disorder 2024-06-13 no assertion criteria provided clinical testing The MC4R c.523G>A variant is predicted to result in the amino acid substitution p.Ala175Thr. This variant was previously reported in affected members of a family with severe familial obesity (Yeo et al. 2003. PubMed ID: 12588803) and in an apparently unrelated proband with severe obesity (Alfieri et al. 2010. PubMed ID: 20214954). However, this variant was also reported in unaffected control cohorts (Carlton et al. 2009. PubMed ID: 19091795) and has a minor allele frequency of up to ~1.0% in sub-populations in one large population database, including 1 homozygote. In vitro studies regarding the resulting function of the p.Ala175Thr variant protein are conflicting, with some authors reporting a mild reduction in activity or expression, and others reporting no change from wild type (Yeo et al. 2003. PubMed ID: 12588803; Farooqi et al. 2003. PubMed ID: 12646665; Mühlhaus et al. 2012. PubMed ID: 22688572; Lotta et al. 2019. PubMed ID: 31002796). At this time, the clinical significance of this variant is classified as uncertain due to the absence of conclusive functional and genetic evidence.

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