ClinVar Genomic variation as it relates to human health
NM_005912.3(MC4R):c.508A>G (p.Ile170Val)
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.
Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005912.3(MC4R):c.508A>G (p.Ile170Val)
Variation ID: 14323 Accession: VCV000014323.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.32 18: 60371842 (GRCh38) [ NCBI UCSC ] 18: 58039075 (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 May 18, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005912.3:c.508A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005903.2:p.Ile170Val missense NM_005912.2:c.508A>G NC_000018.10:g.60371842T>C NC_000018.9:g.58039075T>C NG_016441.1:g.5927A>G LRG_1346:g.5927A>G LRG_1346t1:c.508A>G LRG_1346p1:p.Ile170Val P32245:p.Ile170Val - Protein change
- I170V
- Other names
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- Canonical SPDI
- NC_000018.10:60371841:T:C
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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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0.00080 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00024
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000015399.26 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV003546455.1 | |
MC4R-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jul 21, 2023 | RCV003407337.4 |
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
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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
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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MC4R-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114913.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MC4R c.508A>G variant is predicted to result in the amino acid substitution p.Ile170Val. This variant has been reported in several individuals with severe obesity; … (more)
The MC4R c.508A>G variant is predicted to result in the amino acid substitution p.Ile170Val. This variant has been reported in several individuals with severe obesity; however, its role in pathogenesis has been controversial. It was originally described in two apparently unrelated patients with a BMI >30, and was found to marginally compromise receptor surface localization and function in vitro (Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier. 2006. PubMed ID: 16507637). Since then a significant number of studies have shown that it imparts no change to cell surface expression, ligand binding, or cAMP signaling (See for example, He. 2014. PubMed ID: 25332687; Clément et al. 2018. PubMed ID: 29736023, Supp Table 5). It was found to be a common variant among South African individuals with obesity (2%; n=9;); however, a match control cohort was not included (Logan. 2016. PubMed ID: 26788538). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Oct 13, 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: SCV004265005.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the MC4R protein (p.Ile170Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the MC4R protein (p.Ile170Val). This variant is present in population databases (rs121913560, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of MC4R-related obesity (PMID: 10903341, 11487744, 18559663, 19011902, 26788538, 31751304, 31980526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14323). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 10903341, 12690102, 12959994, 16752916, 19011902, 25332687, 29736023). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Nov 11, 2023)
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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: SCV004183495.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Uncertain significance
(Apr 04, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810106.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Aug 01, 2001)
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no assertion criteria provided
Method: literature only
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OBESITY (BMIQ20)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035660.3
First in ClinVar: Apr 04, 2013 Last updated: May 06, 2019 |
Comment on evidence:
In 1 of 63 obese (BMIQ20; 618406) children, Dubern et al. (2001) identified an A-to-G transition at nucleotide 508 of the MC4R gene, resulting in … (more)
In 1 of 63 obese (BMIQ20; 618406) children, Dubern et al. (2001) identified an A-to-G transition at nucleotide 508 of the MC4R gene, resulting in an isoleucine-to-valine substitution at codon 170 in the fourth transmembrane domain of the melanocortin-4 receptor. (less)
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Pathogenic
(May 01, 2020)
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no assertion criteria provided
Method: clinical testing
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
Affected status: yes
Allele origin:
unknown
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Imperial College London Diabetes Centre, Mubadala Healthcare
Accession: SCV002014765.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Arab
Geographic origin: United Arab Emirates
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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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Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Genetic investigation of patients with tall stature. | Vasco de Albuquerque Albuquerque E | European journal of endocrinology | 2020 | PMID: 31751304 |
MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. | Clément K | Nature medicine | 2018 | PMID: 29736023 |
Allelic variants of the Melanocortin 4 receptor (MC4R) gene in a South African study group. | Logan M | Molecular genetics & genomic medicine | 2015 | PMID: 26788538 |
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 |
Increased constraints on MC4R during primate and human evolution. | Hughes DA | Human genetics | 2009 | PMID: 19011902 |
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 |
Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. | Tao YX | Endocrinology | 2003 | PMID: 12959994 |
Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. | Nijenhuis WA | The Journal of biological chemistry | 2003 | PMID: 12690102 |
Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. | Dubern B | The Journal of pediatrics | 2001 | PMID: 11487744 |
Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. | Vaisse C | The Journal of clinical investigation | 2000 | PMID: 10903341 |
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Text-mined citations for rs121913560 ...
HelpRecord last updated May 19, 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.