Submissions for variant NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)

gnomAD frequency: 0.00001  dbSNP: rs747681609

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000332082	SCV000409977	pathogenic	Obesity	2017-04-28	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000332082	SCV001423086	likely pathogenic	Obesity	2020-01-22	criteria provided, single submitter	curation	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).
MGZ Medical Genetics Center	RCV002288974	SCV002580767	likely pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV003556341	SCV004297609	pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	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.