Submissions for variant NM_005912.3(MC4R):c.485C>T (p.Thr162Ile)

dbSNP: rs1555691402

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001027999	SCV001521754	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2020-06-08	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV000596154	SCV002069277	likely pathogenic	not provided	2019-01-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MC4R gene demonstrated a sequence change, c.485C>T, in exon 1 that results in an amino acid change, p.Thr162Ile, in the apparent homozygous state. This sequence change affects a highly conserved amino acid residue located in a domain of the MC4R protein that is known to be functional. The p.Thr162Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in the heterozygous and homozygous state in patients with severe early-onset obesity (Tan et al., 2009). Functional studies have also demonstrated impaired cell surface trafficking, and reduced ability to generate cAMP in response to ligand (Tan et al. 2009).
GeneDx	RCV000596154	SCV005325083	likely pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant reduction in cell surface expression and signaling response (Tan et al., 2009; He et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20826565, 25332687, 31002796, 35095762, 18801902, 23431915)
Eurofins Ntd Llc (ga)	RCV000596154	SCV000705095	uncertain significance	not provided	2017-01-24	flagged submission	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001027999	SCV001190760	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2020-02-05	no assertion criteria provided	clinical testing
Imperial College London Diabetes Centre, Mubadala Healthcare	RCV001027999	SCV002014763	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2020-05-01	no assertion criteria provided	clinical testing