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).
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 13
- First in ClinVar:
- Apr 4, 2013
- Most recent Submission:
- Aug 5, 2023
- Last evaluated:
- Jul 21, 2023
- Accession:
- VCV000014318.18
- Variation ID:
- 14318
- Description:
- single nucleotide variant
Help
NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)
- Allele ID
- 29357
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 18q21.32
- Genomic location
- 18: 60372245 (GRCh38) GRCh38 UCSC
- 18: 58039478 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005912.3:c.105C>A MANE Select NP_005903.2:p.Tyr35Ter nonsense NC_000018.10:g.60372245G>T NC_000018.9:g.58039478G>T NG_016441.1:g.5524C>A LRG_1346:g.5524C>A LRG_1346t1:c.105C>A LRG_1346p1:p.Tyr35Ter - Protein change
- Y35*
- Other names
- -
- Canonical SPDI
- NC_000018.10:60372244:G:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- The Genome Aggregation Database (gnomAD), exomes 0.00007
- The Genome Aggregation Database (gnomAD) 0.00013
- Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Trans-Omics for Precision Medicine (TOPMed) 0.00011
- Exome Aggregation Consortium (ExAC) 0.00005
- Links
- ClinGen: CA214751
- OMIM: 155541.0003
- dbSNP: rs13447324
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 5 | criteria provided, multiple submitters, no conflicts | Jan 22, 2020 | RCV000015394.37 | |
| Pathogenic | 5 | criteria provided, multiple submitters, no conflicts | Jul 21, 2023 | RCV000255005.10 | |
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Dec 27, 2021 | RCV002504792.2 | |
| Uncertain significance | 1 | no assertion criteria provided | Dec 23, 2014 | RCV000202583.2 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Aug 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000862775.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447336.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Gingivitis (present) , Intellectual disability (present) , Global developmental delay (present) , Recurrent fever (present) , Recurrent infections (present) , Increased body weight (present) , … (more)
Gingivitis (present) , Intellectual disability (present) , Global developmental delay (present) , Recurrent fever (present) , Recurrent infections (present) , Increased body weight (present) , Agranulocytosis (present) , Noncompaction cardiomyopathy (present) , Recurrent pharyngitis (present) (less)
Sex: female
|
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001423111.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 04, 2022 |
Comment:
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 … (more)
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). (less)
|
|
|
pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052811.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 4
Observation 3:
Number of individuals with the variant: 4
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 13
Observation 6:
Tissue: Blood
Observation 7:
Tissue: Blood
|
|
|
Pathogenic
(Dec 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
PerkinElmer Genomics
Accession: SCV003823512.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
|
|
|
Pathogenic
(Jul 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321871.9
First in ClinVar: Oct 09, 2016 Last updated: Aug 05, 2023 |
Comment:
Reported multiple times in association with obesity (Hinney et al., 1999; Hinney et al., 2003; Larsen et al., 2005; Lubrano-Berthelier et al., 2006; Stutzmann et … (more)
Reported multiple times in association with obesity (Hinney et al., 1999; Hinney et al., 2003; Larsen et al., 2005; Lubrano-Berthelier et al., 2006; Stutzmann et al., 2008); Published functional studies demonstrate that Y35X leads to impaired cAMP responses and absent binding of NDP-alphaMSH (Hinney et al., 2003; Larsen et al., 2005); Nonsense variant predicted to result in protein truncation, as the last 298 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 19091795, 16752916, 12970296, 18559663, 16507637, 15486053, 29273807, 29970488, 10199800, 31447099, 10577903, 19301229, 20966905, 12646665, 18801902, 16616374, 16274851) (less)
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000409981.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811048.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Dec 23, 2014)
|
no assertion criteria provided
Method: case-control
|
Affected status: yes
Allele origin:
germline
|
UCL Genetics Institute, UCL
Study: UK10K
Accession: SCV000257527.2 First in ClinVar: Dec 21, 2015 Last updated: Dec 21, 2015
Comment:
In UK10K, seen in 0/982 subjects with severe childhood onset obesity against 1/1392 subjects with schizophrenia
|
Ethnicity/Population group: White european
Geographic origin: United Kingdom
|
|
|
Pathogenic
(Nov 06, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692294.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733802.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917644.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929200.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic obesity: next-generation sequencing results of 1230 patients with obesity. | Kleinendorst L | Journal of medical genetics | 2018 | PMID: 29970488 |
| Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. | Turcot V | Nature genetics | 2018 | PMID: 29273807 |
| Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children. | van den Berg L | Obesity (Silver Spring, Md.) | 2011 | PMID: 20966905 |
| Mutations in the melanocortin 4 receptor (MC4R) gene in obese patients in Norway. | Wangensteen T | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2009 | PMID: 19301229 |
| Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study. | Calton MA | Human molecular genetics | 2009 | PMID: 19091795 |
| Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. | Tan K | Endocrinology | 2009 | PMID: 18801902 |
| Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. | Stutzmann F | Diabetes | 2008 | PMID: 18559663 |
| Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. | Xiang Z | Biochemistry | 2006 | PMID: 16752916 |
| Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. | Tao YX | Pharmacology & therapeutics | 2006 | PMID: 16616374 |
| Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. | Lubrano-Berthelier C | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16507637 |
| Obesity-associated mutations in the human melanocortin-4 receptor gene. | MacKenzie RG | Peptides | 2006 | PMID: 16274851 |
| Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. | Larsen LH | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15486053 |
| Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. | Hinney A | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12970296 |
| Molecular genetics of human obesity-associated MC4R mutations. | Lubrano-Berthelier C | Annals of the New York Academy of Sciences | 2003 | PMID: 12851297 |
| Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. | Farooqi IS | The New England journal of medicine | 2003 | PMID: 12646665 |
| Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. | Lubrano-Berthelier C | Human molecular genetics | 2003 | PMID: 12499395 |
| Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. | Sina M | American journal of human genetics | 1999 | PMID: 10577903 |
| Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. | Hinney A | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10199800 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MC4R | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a7c7f38f-e9ef-4d21-8dde-07ad46890ebe | - | - | - | - |
Text-mined citations for rs13447324...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Aug 06, 2023