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

gnomAD frequency: 0.00005  dbSNP: rs549442687

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	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)