Submissions for variant NM_005912.3(MC4R):c.913C>T (p.Arg305Trp)

gnomAD frequency: 0.00005  dbSNP: rs549442687

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000712270	SCV000842720	likely pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249094	SCV001423116	uncertain significance	Obesity	2020-01-22	criteria provided, single submitter	curation	The p.Arg305Trp variant in MC4R has been reported in 2 individuals (including 1 Jamaican individual) with Obesity (PMID: 16507637, 20696697; Alsters 2016), and has been identified in 0.01129% (4/35436) of Latino chromosomes and 0.006533% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549442687). 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 in ClinVar (Variation ID: 586138). In vitro functional studies provide some evidence that the p.Arg305Trp variant may impact protein function (PMID: 16507637, 20696697). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PS4_Supporting (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV000712270	SCV002067354	pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing	DNA sequence and deletion/duplication analysis of the MC4R gene demonstrated a sequence change, c.913C>T, in exon 1 that results in an amino acid change, p.Arg305Trp. The p.Arg305Trp change has been identified in three individuals with obesity (PMIDs: 29970488, 20696697, 16507637). The p.Arg305Trp change was found to be a de novo change in one of these individuals (PMID 29970488). This sequence change has been described in the gnomAD database with a frequency of 0.011% in Latino populations (dbSNP rs549442687). The p.Arg305Trp change affects a highly conserved amino acid residue located in a domain of the MC4R protein that is known to be functional. The p.Arg305Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated that this sequence change results in both reduced basal activity and _-MSH potency (PMID: 20696697, 16507637).
GeneDx	RCV000712270	SCV003936738	likely pathogenic	not provided	2022-12-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: R305W has decreased membrane expression and basal activity (Lubrano-Berthelier et al., 2006; Roubert et al., 2010); Identified in the heterozygous state in patients with obesity in published literature (Abawi et al., 2022; Kleinendorst et al., 2018; Lubrano-Berthelier et al., 2006; Polk et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12851297, 18559663, 20696697, 16507637, 29970488, 35898454, 29031731, 32952152, 28284973, 31417496, 26119161, 26244670)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017723	SCV004847625	likely pathogenic	Obesity due to melanocortin 4 receptor deficiency	2022-02-25	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000712270	SCV005838620	uncertain significance	not provided	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 305 of the MC4R protein (p.Arg305Trp). This variant is present in population databases (rs549442687, gnomAD 0.01%). This missense change has been observed in individual(s) with obesity (PMID: 12851297, 16507637, 18559663, 20696697, 29970488). ClinVar contains an entry for this variant (Variation ID: 586138). 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 have shown that this missense change affects MC4R function (PMID: 16507637, 18559663, 20696697). 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.
PreventionGenetics, part of Exact Sciences	RCV004748911	SCV005360472	likely pathogenic	MC4R-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The MC4R c.913C>T variant is predicted to result in the amino acid substitution p.Arg305Trp. This variant has been reported in the heterozygous state in a number of patients with obesity, including one with a de novo variant (Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Stutzmann et al. 2008. PubMed ID: 18559663; Kleinendorst et al. 2018. PubMed ID: 29970488). Functional studies have shown that the c.913C>T variant leads to a reduction in protein function (Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Stutzmann et al. 2008. PuMed ID: 18559663; Roubert et al. 2010. PubMed ID: 20696697). A different substitution at the same amino acid (p.Arg305Gln) has also been reported to cause obesity (see for example Reinehr et al. 2009. PubMed ID: 18997677). Taken together, we consider the evidence sufficient to classify the c.913C>T (p.Arg305Trp) variant found in this patient as likely pathogenic.