ClinVar Miner

Submissions for variant NM_005912.3(MC4R):c.380C>T (p.Ser127Leu) (rs13447331)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000015412 SCV000409978 uncertain significance Obesity 2017-04-27 criteria provided, single submitter clinical testing The MC4R c.380C>T (p.Ser127Leu) variant has been identified in a heterozygous state in six individuals and in a compound heterozygous state in nine individuals with obesity with a known polymorphism in the MC4R gene (Hinney et al. 2003; Valli-Jaakola et al. 2004; Hainerova et al. 2007; Calton et al. 2009; Santoro et al. 2009; Nowacka-Woszuk et al. 2011; Albuquerque et al. 2014; Rovite et al. 2014). The variant is also found in five unaffected individuals, including two that carried the variant in a compound heterozygous state with a common MC4R polymorphism (Nowacka-Woszuk et al. 2011; Rouskas et al. 2012; Stanikova et al. 2015). Functional studies for the p.Ser127Leu variant revealed a constituitively active receptor (Hinney et al. 2003; Srinivasan et al. 2007; Mo et al. 2013; ), which conflicts with functional studies showing decreased cell surface expression (Rovite et al. 2014), impaired signaling (Valli-Jaakola et al. 2004), and altered alpha-MSH activation of the receptor (Lubrano-Berthelier et al. 2003). The p.Ser127eu variant is reported at a frequency of 0.00052 in the Latino population of the Exome Aggregation Consortium. Based on the conflicting evidence from the literature, the p.Ser127Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000414065 SCV000491324 likely pathogenic not provided 2016-01-07 criteria provided, single submitter clinical testing The S127L variant in the MC4R gene has been reported in individuals with obesity (Lubrano-Berthelier et al., 2003; Rovite et al., 2014). Functional assays showed S127L has decreased membrane trafficking and functional activity (Rovite et al., 2014). The S127L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S127L variant is a non-conservative amino acid substitution, which occurs within the Transmembrane 3 domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (D126Y) has been reported in the Human Gene Mutation Database in association with obesity (Stenson et al., 2014), supporting the functional importance of this region of the protein. The S127L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414065 SCV000705333 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000015412 SCV000840007 likely pathogenic Obesity 2017-05-25 criteria provided, single submitter clinical testing This c.380C>T (p.Ser127Leu) variant in the MC4R gene has previously been reported in multiple patients presenting with obesity [PMID 12499395, 24385306, 18559663, 14764818, 26047380]. The variant was also detected in one lean individual, the mother of the obese proband, indicating possible incomplete penetrance [PMID 26047380]. Functional assays showed that the receptor displayed high constitutive activity [PMID 19298524, 12970296]. However, cell surface expression level of the p.Ser127Leu mutant was decreased by about half of wild type [PMID 19298524, 24385306]. Thus, the mechanism of pathogenicity for this variant in unclear at this time. Serine at amino acid position 127 of the MC4R protein is highly conserved in mammals. This variant has been observed in 20 heterozygous individuals from the ExAC database ( While not validated for clinical use, the computer-based algorithms SIFT and Polyphen2 predict this p.Ser127Leu change to be deleterious. It is thus interpreted as a likely pathogenic variant.
Athena Diagnostics Inc RCV000414065 SCV000842715 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease in genotyped family members (p < 0.05), and data are from multiple families. One de novo case with parental identity confirmed.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414065 SCV001371375 likely pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
OMIM RCV000768580 SCV000035673 pathogenic BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 2004-02-01 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000015412 SCV001423112 likely pathogenic Obesity 2020-01-22 no assertion criteria provided curation The p.Ser127Leu variant in MC4R has been reported in 30 individuals (including 3 German, 3 Latvian, 2 Polish, 2 Iberian, 2 Finnish, 1 Slovak and 1 Czech individuals) who are overweight or have Obesity (PMID: 14764818, 17579204, 12499395, 23146882, 12970296, 24385306, 26047380, 24611737, 18559663, 19284607, 21404042, 19091795, 17357083), and has been identified in 0.1157% (12/10370) of Ashkenazi Jewish chromosomes and 0.02090% (27/129176) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs13447331). 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 pathogenic variant in ClinVar (Variation ID: 14336). In vitro functional studies provide some evidence that the p.Ser127Leu variant may impact protein function (PMID: 14764818, 12499395, 16752916, 12970296, 23791567, 19298524). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_moderate (Richards 2015).

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