Submissions for variant NM_005912.3(MC4R):c.835_836dup (p.Phe280fs)

dbSNP: rs193922687

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030159	SCV000052817	pathogenic	Obesity	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000030159	SCV001422867	likely pathogenic	Obesity	2020-01-22	criteria provided, single submitter	curation	The p.Phe280Alafs variant in MC4R has been reported in at least 4 individuals from the UK with obesity, segregated with disease in at these four affected relatives from two families (PMID: 18801902,12646665), and has been identified in 0.0009% (1/113664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922687). This variant has also been reported in ClinVar as pathogenic (Variation ID: 36487). In vitro functional studies provide evidence that the p.Phe280Alafs variant may impact protein function (PMID: 12646665). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 280 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated protein since this is a single exon gene that is not predicted to undergo nonsense mediated decay. Heterozygous loss of function of the MC4R gene is an established disease mechanism in obesity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PVS1_strong, PM2_supporting, PP1, PS4_supporting (Richards 2015).
GeneDx	RCV002281046	SCV002569651	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	Identified in two unrelated individuals with early-onset obesity in the published literature (Farooqi et al., 2003); Frameshift variant predicted to result in protein truncation, as the last 53 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies show the variant results in loss of function (Farooqi et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16752916, 24077912, 12646665, 10903343)
Fulgent Genetics, Fulgent Genetics	RCV002496462	SCV002810449	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-07-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415745	SCV004116589	pathogenic	MC4R-related condition	2024-02-06	criteria provided, single submitter	clinical testing	The MC4R c.835_836dupTG variant is predicted to result in a frameshift and premature protein termination (p.Phe280Alafs*12). This variant has been reported to be causative for severe early onset obesity (reported as insertion of GT at codon 279 in Farooqi et al. 2000. PubMed ID: 10903343; Farooqi et al. 2003. PubMed ID: 12646665). An in vitro functional study showed no activity of the protein (Farooqi et al. 2003. PubMed ID: 12646665). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MC4R are expected to be pathogenic. This variant is interpreted as pathogenic.