NM_005912.3:c.380C>T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5
The NM_005912.3(MC4R):c.380C>T(p.Ser127Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.380C>T | p.Ser127Leu | missense_variant | Exon 1 of 1 | 6 | NM_005912.3 | ENSP00000299766.3 | ||
ENSG00000285681 | ENST00000650201.1 | n.113+42625G>A | intron_variant | Intron 1 of 3 | ||||||
ENSG00000285681 | ENST00000658928.1 | n.156+42625G>A | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000171 AC: 43AN: 251366Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135868
GnomAD4 exome AF: 0.000120 AC: 175AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 727218
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:5Uncertain:1
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This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 127 of the MC4R protein (p.Ser127Leu). This variant is present in population databases (rs13447331, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal dominant severe obesity (PMID: 12499395, 12970296, 14764818, 18559663, 24385306, 24611737, 26238496, 30926952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14336). 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 not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 12970296, 14764818, 22447289, 24385306). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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. -
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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. -
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:4
_x000D_ Criteria applied: PS3, PS4_MOD -
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Obesity Pathogenic:2Uncertain:1
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. -
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, http://gnomad.broadinstitute.org; 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). -
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 (http://exac.broadinstitute.org/variant/18-58039203-G-A). 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. -
Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
MC4R-related disorder Pathogenic:1
The MC4R c.380C>T variant is predicted to result in the amino acid substitution p.Ser127Leu. This variant has been identified in the heterozygous state in multiple individuals with obesity (Lubrano-Berthelier et al. 2004. PubMed ID: 15126516; Stutzmann et al. 2008. PubMed ID: 18559663; Stankiova et al. 2015. PubMed ID: 26047380). However, it has also been described in lean individuals (Stankiova et al. 2015. PubMed ID: 26047380; Rouskas et al. 2012. PubMed ID: 22447289). Multiple functional studies testing this variant have shown that it alters the protein’s biophysical properties and cell surface expression (for a review see Fan and Tao. 2009. PubMed ID: 19298524). This variant is interpreted as likely pathogenic in ClinVar by the vast majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/14336/). Based on the collective information, we interpret this variant as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at