Submissions for variant NM_019888.3(MC3R):c.892_893delinsTC (p.Ile298Ser)

dbSNP: rs2146061616

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002002256	SCV002227536	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the MC3R protein (p.Ile298Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with MC3R-related conditions (PMID: 17964765, 21047972, 35574020, 37369769). This variant is also known as I335S. ClinVar contains an entry for this variant (Variation ID: 1448476). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MC3R function (PMID: 17964765, 21047972, 25798062). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002002256	SCV002563688	likely pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004749808	SCV005349516	uncertain significance	MC3R-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The MC3R c.892_893delinsTC variant is predicted to result in an in-frame deletion and insertion. This variant was reported in individuals with obesity (described as I335S in Table 1, Tao et al. 2007. PubMed ID: 17964765; Zheng et al. 2023. PubMed ID: 37369769). The p.Ile298Ser alternation was also documented in additional obese individuals (Mencarelli et al. 2008. PubMed ID: 18231126; Mencarelli et al. 2011. PubMed ID: 21047972). Functional studies suggested that the p.Ile298Ser substitution results in intracellular retention, altered cAMP signaling upon α-MSH stimulation, and loss of ligand binding (Tao et al. 2007. PubMed ID: 17964765; Mencarelli et al. 2008. PubMed ID: 18231126; Yang et al. 2015. PubMed ID: 25798062). In gnomAD, this variant is documented separately as two variants, c.892A>T and c.893T>C, and the two variants are reported to be on the same allele in 37 heterozygous individuals (https://gnomad.broadinstitute.org/variant-cooccurrence?dataset=gnomad_r2_1&variant=20-54824791-A-T&variant=20-54824792-T-C). At this time, the clinical significance of the c.892_893delinsTC (p.Ile298Ser) variant is uncertain.