Submissions for variant NM_005912.3(MC4R):c.508A>G (p.Ile170Val)

gnomAD frequency: 0.00016  dbSNP: rs121913560

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000015399	SCV004183495	likely pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2023-11-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003546455	SCV004265005	uncertain significance	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the MC4R protein (p.Ile170Val). This variant is present in population databases (rs121913560, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of MC4R-related obesity (PMID: 10903341, 11487744, 18559663, 19011902, 26788538, 31751304, 31980526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14323). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 10903341, 12690102, 12959994, 16752916, 19011902, 25332687, 29736023). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000015399	SCV004810106	uncertain significance	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000015399	SCV000035660	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2001-08-01	no assertion criteria provided	literature only
Imperial College London Diabetes Centre, Mubadala Healthcare	RCV000015399	SCV002014765	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2020-05-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407337	SCV004114913	uncertain significance	MC4R-related disorder	2024-09-12	no assertion criteria provided	clinical testing	The MC4R c.508A>G variant is predicted to result in the amino acid substitution p.Ile170Val. This variant has been reported in several individuals with severe obesity; however, its role in pathogenesis has been controversial. It was originally described in two apparently unrelated patients with a BMI >30, and was found to marginally compromise receptor surface localization and function in vitro (Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier. 2006. PubMed ID: 16507637). Since then a significant number of studies have shown that it imparts no change to cell surface expression, ligand binding, or cAMP signaling (See for example, He. 2014. PubMed ID: 25332687; Clément et al. 2018. PubMed ID: 29736023, Supp Table 5). It was found to be a common variant among South African individuals with obesity (2%; n=9;); however, a match control cohort was not included (Logan. 2016. PubMed ID: 26788538). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD. Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.