ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.239A>G (p.Tyr80Cys)

gnomAD frequency: 0.00001  dbSNP: rs1368643838
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000499779 SCV000595719 uncertain significance not specified 2015-10-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001857128 SCV002119054 uncertain significance not provided 2021-12-06 criteria provided, single submitter clinical testing This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 80 of the MC4R protein (p.Tyr80Cys). This variant has not been reported in the literature in individuals affected with MC4R-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 435830).
Fulgent Genetics, Fulgent Genetics RCV002490836 SCV002778959 uncertain significance BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 2021-12-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003409696 SCV004113390 uncertain significance MC4R-related disorder 2024-07-16 no assertion criteria provided clinical testing The MC4R c.239A>G variant is predicted to result in the amino acid substitution p.Tyr80Cys. This variant was reported in an individual from a UK birth cohort study of MC4R variants; however, detailed clinical information of the individual was not provided (Wade et al. 2021. PubMed ID: 34045736). In vitro functional studies suggest that the p.Tyr80Cys substitution could impact normal protein function (Wade et al. 2021. PubMed ID: 34045736, Figure 1e and Extended Data Figure 2b). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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