Submissions for variant NM_005912.3(MC4R):c.181G>A (p.Glu61Lys)

gnomAD frequency: 0.00001  dbSNP: rs370479598

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501559	SCV000595720	likely pathogenic	Obesity, autosomal dominant	2015-10-26	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000518806	SCV000614059	pathogenic	not provided	2016-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000518806	SCV001826572	likely pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Tan et al., 2009); This variant is associated with the following publications: (PMID: 20462274, 18801902, 20826565, 19091795, 34662886, 17357083)
Revvity Omics, Revvity	RCV003144296	SCV003832346	likely pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2023-11-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409697	SCV004107463	pathogenic	MC4R-related condition	2024-01-08	criteria provided, single submitter	clinical testing	The MC4R c.181G>A variant is predicted to result in the amino acid substitution p.Glu61Lys. This variant has been reported in the heterozygous state in at least two individuals with severe early-onset obesity (Ahituv et al. 2007. PubMed ID: 17357083; Calton et al. 2009. PubMed ID: 19091795). In vitro studies indicate that this variant causes intracellular retention, decreased ligand binding, and reduced downstream cellular signaling (René et al. 2010. PubMed ID: 20826565; Tan et al. 2009. PubMed ID: 18801902; Xiang et al. 2010. PubMed ID: 20462274). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We interpret this variant as pathogenic.
Invitae	RCV000518806	SCV004267565	likely pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MC4R function (PMID: 17357083, 18801902). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 435831). This missense change has been observed in individual(s) with autosomal dominant obesity (PMID: 17357083, 18801902, 33761344). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs370479598, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 61 of the MC4R protein (p.Glu61Lys).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583759	SCV000692297	pathogenic	Obesity	2013-12-19	no assertion criteria provided	clinical testing