ClinVar Genomic variation as it relates to human health
NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)
Variation ID: 14318 Accession: VCV000014318.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.32 18: 60372245 (GRCh38) [ NCBI UCSC ] 18: 58039478 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Dec 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005912.3:c.105C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
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
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- Canonical SPDI
- NC_000018.10:60372244:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00013
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MC4R | - | - |
GRCh38 GRCh37 |
165 | 239 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2020 | RCV000015394.38 | |
Uncertain significance (1) |
no assertion criteria provided
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Dec 23, 2014 | RCV000202583.2 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2023 | RCV000255005.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2021 | RCV002504792.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Obesity
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
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)
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Pathogenic
(Nov 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811048.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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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)
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Pathogenic
(Dec 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297611.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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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
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inherited obesity
Affected status: unknown
Allele origin:
germline
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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)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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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
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pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Early Onset Obesity
(autosomal dominant)
Affected status: yes, unknown
Allele origin:
germline
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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
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Pathogenic
(Dec 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003823512.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 23, 2014)
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no assertion criteria provided
Method: case-control
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Schizophrenia
Affected status: yes
Allele origin:
germline
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UCL Genetics Institute, UCL
Study: UK10K
Accession: SCV000257527.2 First in ClinVar: Dec 21, 2015 Last updated: Dec 21, 2015 |
Ethnicity/Population group: White european
Geographic origin: United Kingdom
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Pathogenic
(Nov 06, 2013)
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no assertion criteria provided
Method: clinical testing
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Obesity
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692294.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Inherited obesity
Affected status: yes
Allele origin:
germline
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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 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. | Nijenhuis WA | The Journal of biological chemistry | 2003 | PMID: 12690102 |
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 |
Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. | Vaisse C | The Journal of clinical investigation | 2000 | PMID: 10903341 |
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 | - | - | - | - |
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Text-mined citations for rs13447324 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.