Submissions for variant NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)

gnomAD frequency: 0.00013  dbSNP: rs13447324

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015394	SCV000052811	pathogenic	Obesity	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000255005	SCV000321871	pathogenic	not provided	2024-09-25	criteria provided, single submitter	clinical testing	Reported multiple times in association with obesity (PMID: 10199800, 12970296, 15486053, 16507637, 18559663); Published functional studies demonstrate that Y35X leads to impaired cAMP responses and absent binding of NDP-alphaMSH (PMID: 12970296, 15486053); Nonsense variant predicted to result in protein truncation, as the last 298 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 19091795, 16752916, 18559663, 16507637, 15486053, 29273807, 29970488, 31447099, 10577903, 19301229, 20966905, 12646665, 18801902, 16616374, 16274851, 36325899, 34083135, 10199800, 12970296, 37601970)
Illumina Laboratory Services, Illumina	RCV000015394	SCV000409981	pathogenic	Obesity	2017-04-27	criteria provided, single submitter	clinical testing	The MC4R c.105C>A (p.Tyr35Ter) stop-gained variant has been identified in a heterozygous state in at least 38 individuals with obesity. In almost all of these reports, the variant was found in cis with another variant, p.Asp37Val (Hinney et al. 1999; Hinney et al. 2003; Farooqi et al. 2003; Stutzmann et al. 2008; Tan et al. 2009; Calton et al. 2009; Larsen et al. 2009; van den Berg et al. 2011). The p.Tyr35Ter variant was absent from over 4,000 controls and is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Lubrano-Berthelier et al. (2006) demonstrated a complete lack of membrane expression of the p.Tyr35Ter variant protein as well as a significantly impaired basal receptor activity and reduced response to a receptor agonist, both to less than 10% of wildtype. It has been shown that the C-terminal tail of the receptor contains a signal for cell surface expression, hence any truncation of the protein upstream of this signal as is predicted for the p.Tyr35Ter variant would result in intracellular retention of the variant receptor (MacKenzie, 2006). Based on the collective evidence and the potential impact of stop-gained variants, the p.Tyr35Ter variant is classified as pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Eurofins Ntd Llc (ga)	RCV000255005	SCV000862775	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000015394	SCV001423111	pathogenic	Obesity	2020-01-22	criteria provided, single submitter	curation	The p.Tyr35Ter variant in MC4R has been reported in at least 46 individuals (including 9 Danish, 5 German, 3 Dutch, and 1 Norweigan individuals) with Obesity (PMID: 10199800, 19301229, 15486053, 12970296, 16507637, 20966905, 10577903, 18801902, 18559663, 19091795), and has been identified in 0.01549% (20/129114) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447324). This variant was also reported in a non-obese and non-overweight individual (PMID: 10577903). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar, and is often reported in cis with the p.Asp37Val variant (Variation ID: 14318). In vitro functional studies provide some evidence that the p.Tyr35Ter variant may eliminate receptor activity and cell membrane expression (PMID: 16507637, 20966905). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 35. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without regions important to function. Heterozygous loss of function of the MC4R gene is an established disease mechanism in Obesity. In summary, this variant meets criteria to be classified as pathogenic for Obesity in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Obesity. ACMG/AMP Criteria applied: PVS1_Strong, PS4, PS3, PM2_Supporting (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255005	SCV001447336	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504792	SCV002811048	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-11-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002504792	SCV003823512	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2021-12-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255005	SCV004297611	pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr35*) in the MC4R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 298 amino acid(s) of the MC4R protein. This variant is present in population databases (rs13447324, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features consistent with MC4R-related obesity (PMID: 10199800, 12970296, 15486053, 29970488). ClinVar contains an entry for this variant (Variation ID: 14318). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MC4R function (PMID: 12970296, 16507637, 16752916). This variant disrupts a region of the MC4R protein in which other variant(s) (p.Ile301Thr) have been determined to be pathogenic (PMID: 10903341, 12690102, 16507637, 16752916, 18559663). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017247	SCV004848238	pathogenic	Obesity due to melanocortin 4 receptor deficiency	2018-09-19	criteria provided, single submitter	clinical testing	The p.Tyr35X variant in MC4R has been reported in >15 individuals with obesity and segregated with disease in at least 8 relatives (Hinney 1999, Sina 1999, Hinney 2003, Larsen 2005, Lubrano-Berthelier 2006, Stutzmann 2008, Wangensteen 2009, Calton 2009, van den Berg 2011). The Tyr35X variant has been identified in 20/126634 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447324). This variant leads to a premature termination codon at position 35, which is predicted to lead to a truncated or absent protein. Please note, this variant is commonly seen in cis (on same allele) with p.Asp37Val, which would not be translated since it is downstream of the premature stop codon. In vitro expression of the p.Tyr35X-MC4R protein demonstrated absent cell surface expression, ligand binding, and cAMP response (Larsen 2005, Xiang 2006, Lubrano-Berthelier 2006, Brumm 2012). Haploinsufficiency of the MC4R gene is an established disease mechanism in MC4R-related obesity. In summary, this variant meets criteria to be classified as pathogenic for MC4R-related obesity in an autosomal dominant. ACMG/AMP Criteria applied: PVS1_Strong, PS4, PS3, PP1_Strong.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255005	SCV005198726	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV002504792	SCV005382176	pathogenic	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	2024-09-18	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM2_P, PS3, PP5; Variant was found in a heterozygous state
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004017247	SCV005400000	pathogenic	Obesity due to melanocortin 4 receptor deficiency	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Even though, inheritance is predominantly dominant, homozygotes have higher mean percentage body fat than heterozygotes (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 29970488). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 1 of 1). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (21 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with obesity (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common MC4R variants reported in patients with obesity, usually seen in cis with p.(Asp37Val) due to a founder effect in Europeans, mostly Danish and German (ClinVar, PMID: 15486053, PMID: 12970296, PMID: 12970296). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Studies show that this variant showed no binding to the analog of the endogenous agonist, impairing significantly protein function (PMID: 15486053, PMID: 12851297). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
UCL Genetics Institute, UCL	RCV000202583	SCV000257527	uncertain significance	Schizophrenia	2014-12-23	no assertion criteria provided	case-control
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000015394	SCV000692294	pathogenic	Obesity	2013-11-06	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000015394	SCV000733802	pathogenic	Obesity		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000255005	SCV001917644	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255005	SCV001929200	pathogenic	not provided		no assertion criteria provided	clinical testing