ClinVar Genomic variation as it relates to human health
NM_005912.3(MC4R):c.806T>A (p.Ile269Asn)
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.
Pathogenic(3); Uncertain significance(4); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005912.3(MC4R):c.806T>A (p.Ile269Asn)
Variation ID: 36486 Accession: VCV000036486.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.32 18: 60371544 (GRCh38) [ NCBI UCSC ] 18: 58038777 (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 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005912.3:c.806T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005903.2:p.Ile269Asn missense NC_000018.10:g.60371544A>T NC_000018.9:g.58038777A>T NG_016441.1:g.6225T>A LRG_1346:g.6225T>A LRG_1346t1:c.806T>A LRG_1346p1:p.Ile269Asn - Protein change
- I269N
- Other names
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- Canonical SPDI
- NC_000018.10:60371543:A: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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00081
The Genome Aggregation Database (gnomAD), exomes 0.00103
The Genome Aggregation Database (gnomAD) 0.00011
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00045
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
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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 |
170 | 244 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Uncertain significance (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV000030158.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2019 | RCV000499660.8 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 15, 2024 | RCV000906648.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 22, 2022 | RCV002285259.4 |
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
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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
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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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Uncertain significance
(Jan 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052816.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 08, 2019 |
Comment:
Variant summary: MC4R c.806T>A (p.Ile269Asn) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain of the encoded protein sequence. Four … (more)
Variant summary: MC4R c.806T>A (p.Ile269Asn) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 277298 control chromosomes, predominantly at a frequency of 0.0073 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in MC4R causing Early Onset Obesity phenotype (0.0005), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, c.806T>A has been reported in the literature in multiple individuals affected with Early Onset Obesity (Hohenadel_2014, Tan_2009). Furthermore, at-least two of these reports identified this variant in individuals of Hispanic/Latina ancestry who are enriched for this variant among the control cohorts. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Obesity. Experimental evidence evaluating an impact on protein function demonstrated the variant to have a significantly different EC50 (the concentration of ligand needed to achieve 50% of maximum effect) than that of the wild type (WT) receptor (Thearle_2012, Calton_2009), reduced expression at the cell surface and decreased receptor binding (Hohenadel_2014, Tan_2009) while, it also exhibited defective ligand-stimulated response compared to WT and was determined to have biased signaling in the ERK1/2 pathway (He_2014). Studies were contradictory in terms of cyclic AMP response after agonist administration either detecting loss of function or no significant difference in function compared to WT (Hohenadel_2014, Tan_2009). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the possibility that this is likely to represent a benign variation cannot be excluded. Due to equivocal reports of functional relevance the variant was classified as uncertain significance. (less)
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Benign
(Jan 15, 2024)
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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: SCV001051300.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Pathogenic
(Oct 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001476539.2
First in ClinVar: Jan 26, 2021 Last updated: Sep 19, 2021 |
Comment:
Although the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, this variant … (more)
Although the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, this variant was shown to associate with obesity in Mexican children and adults (PMID:31841602, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments showed reduced cell surface expression and ligand binding, as well as loss of signal transduction (PMID:18801902,24276017,31002796). Computational tools predict that this variant is damaging. (less)
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Uncertain significance
(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: SCV001423113.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Ile269Asn variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 19091795), and has been identified in 0.7309% (259/35438) of Latino … (more)
The p.Ile269Asn variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 19091795), and has been identified in 0.7309% (259/35438) of Latino chromosomes, including 5 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79783591). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 36486). In vitro functional studies provide some evidence that the p.Ile269Asn variant may impact cell surface expression, protein folding, and receptor activation (PMID: 18801902, 19091795). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3, PS4_Supporting (Richards 2015). (less)
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Pathogenic
(Aug 25, 2017)
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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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Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV002576299.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
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Pathogenic
(Feb 07, 2022)
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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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Baylor Genetics
Accession: SCV003836238.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Uncertain significance
(Mar 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595716.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Uncertain significance
(Apr 22, 2022)
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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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New York Genome Center
Accession: SCV003925120.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Clinical Features:
Hyperlipidemia (present) , Hepatic steatosis (present) , Diabetes mellitus (present)
Secondary finding: no
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Pathogenic
(May 23, 2014)
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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: SCV000692303.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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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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Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants. | Namjou B | International journal of obesity (2005) | 2021 | PMID: 32952152 |
A missense variant, p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability. | Beleford DT | European journal of medical genetics | 2020 | PMID: 32534219 |
The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans. | Vázquez-Moreno M | The Journal of clinical endocrinology and metabolism | 2020 | PMID: 31841602 |
Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. | Flannick J | Nature | 2019 | PMID: 31118516 |
Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. | Lotta LA | Cell | 2019 | PMID: 31002796 |
Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity. | De Rosa MC | The Journal of clinical endocrinology and metabolism | 2019 | PMID: 30811542 |
Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene. | He S | International journal of biological sciences | 2014 | PMID: 25332687 |
Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. | Hohenadel MG | International journal of obesity (2005) | 2014 | PMID: 24276017 |
Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians. | Thearle MS | Diabetes | 2012 | PMID: 22106157 |
Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. | Cole SA | The American journal of clinical nutrition | 2010 | PMID: 19889825 |
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 |
Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in the Hispanic population. | Butte NF | The American journal of clinical nutrition | 2006 | PMID: 16960181 |
The human MC4R promoter: characterization and role in obesity. | Lubrano-Berthelier C | Diabetes | 2003 | PMID: 14633862 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/827f4cda-53c3-4166-bfaa-62722cd6eb89 | - | - | - | - |
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Text-mined citations for rs79783591 ...
HelpRecord last updated May 08, 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.