rs747681609
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_005912.3(MC4R):c.494G>A(p.Arg165Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC4R | NM_005912.3 | c.494G>A | p.Arg165Gln | missense_variant | 1/1 | ENST00000299766.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.494G>A | p.Arg165Gln | missense_variant | 1/1 | NM_005912.3 | P1 | ||
ENST00000658928.1 | n.156+42511C>T | intron_variant, non_coding_transcript_variant | |||||||
ENST00000650201.1 | n.113+42511C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251310Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135834
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727238
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
Obesity Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The MC4R c.494G>A (p.Arg165Gln) variant has been reported in at least four studies in a heterozygous state in a total of 18 individuals with severe early-onset obesity, severe obesity, or juvenile onset obesity (Farooqi et al. 2000; Farooqi et al. 2003; Ma et al. 2004; Larsen et al. 2005). In one family, the p.Arg165Gln variant was detected in both the affected father and affected son. The p.Arg165Gln variant was absent from 2,070 control alleles but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the p.Arg165Gln variant was expressed but defective in trafficking to the cell surface and was retained intracellularly. The variant was also shown to have impaired ligand-stimulated ERK 1/2 activation, a partial cAMP response when stimulated with alpha-MSH, and to exhibit a 17-fold decrease in affinity to NDP-MSH as a result of a markedly reduced ligand binding capacity (Nijenhuis et al. 2003; Yeo et al. 2003; He et al. 2014). The Arg165 residue is conserved across thirty species (Staubert et al. 2007). Based on the evidence, the p.Arg165Gln variant is classified as pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg165Gln variant in MC4R has been reported in 20 individuals with Obesity, segregated with disease in 2 affected relatives from one family, (PMID: 10903343, 12646665, 15448103, 15486053, 29861388), and has been identified in 0.005441% (1/18380) of East Asian chromosomes and 0.004399% (5/113650) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747681609). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. 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 likely pathogenic in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact expression, ligand binding, and protein activity (PMID: 12588803, 12690102, 12646665, 15486053, 20826565). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg165Gly, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22106157, 24276017, 25332687). 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, PM2_Supporting, PM5_supporting (Richards 2015). - |
Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 26, 2018 | The p.Arg165Gln variant in MC4R has been reported in >15 individuals with severe obesity and segregated with disease in one affected relative (Farooqi 2003, Ma 2004, Larsen 2005). This variant has been identified in 6/111582 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact protein function (Nijenhuis 2003, Farooqi 2003, Larsen 2005, Xiang 2006, Thearle 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg165Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg165Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_Supporting, PM2_Supporting. - |
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 30, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the MC4R protein (p.Arg165Gln). This variant is present in population databases (rs747681609, gnomAD 0.006%). This missense change has been observed in individual(s) with MC4R-related obesity (PMID: 10903343, 12646665, 15486053, 18835933, 33889637). ClinVar contains an entry for this variant (Variation ID: 327713). 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. Experimental studies have shown that this missense change affects MC4R function (PMID: 12588803, 12690102, 15486053, 16752916, 24276017, 31002796). This variant disrupts the p.Arg165 amino acid residue in MC4R. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10903341, 12690102, 16752916). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at