proposed classification - variant undergoing re-assessment, contact laboratory
ClinVar Genomic variation as it relates to human health
NM_005912.3(MC4R):c.896C>A (p.Pro299His)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(4); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(4); Uncertain significance(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005912.3(MC4R):c.896C>A (p.Pro299His)
Variation ID: 36488 Accession: VCV000036488.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.32 18: 60371454 (GRCh38) [ NCBI UCSC ] 18: 58038687 (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 Dec 7, 2024 Oct 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005912.3:c.896C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005903.2:p.Pro299His missense NC_000018.10:g.60371454G>T NC_000018.9:g.58038687G>T NG_016441.1:g.6315C>A LRG_1346:g.6315C>A LRG_1346t1:c.896C>A LRG_1346p1:p.Pro299His - Protein change
- P299H
- Other names
- -
- Canonical SPDI
- NC_000018.10:60371453: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| MC4R | - | - |
GRCh38 GRCh37 |
236 | 312 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2024 | RCV000030160.3 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 19, 2024 | RCV002281047.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2022 | RCV004017271.1 | |
|
MC4R-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 31, 2024 | RCV003430643.7 |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2023 | RCV001781324.4 |
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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|---|---|---|---|---|---|
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Likely Pathogenic
(Mar 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Obesity due to melanocortin 4 receptor deficiency
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848237.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
|
|
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pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
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Early Onset Obesity
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052818.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 2
Observation 2:
Number of individuals with the variant: 2
Observation 3:
Number of individuals with the variant: 2
Observation 4:
Number of individuals with the variant: 3
Observation 5:
Number of individuals with the variant: 3
Observation 6:
Tissue: Blood
|
|
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Pathogenic
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002801266.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Likely pathogenic
(Nov 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
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BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244448.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PM2
|
|
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Uncertain significance
(Mar 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004297605.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Experimental studies have shown that this missense change affects MC4R function (PMID: 16083993, 16752916, 20696697, 20826565, 25332687). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 36488). This missense change has been observed in individual(s) with obesity (PMID: 12499395, 12851297, 18559663, 19091795, 24426828). This variant is present in population databases (rs52804924, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 299 of the MC4R protein (p.Pro299His). (less)
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Likely pathogenic
(Jun 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002569704.4
First in ClinVar: Sep 10, 2022 Last updated: Sep 29, 2024 |
Comment:
Observed in the apparent homozygous state and also in the heterozygous state with a second MC4R variant, phase unknown, in patients with early-onset obesity in … (more)
Observed in the apparent homozygous state and also in the heterozygous state with a second MC4R variant, phase unknown, in patients with early-onset obesity in the literature and not observed in homozygous state in controls (PMID: 34694010, 24426828, 37814975); Identified in the heterozygous state in patients with early-onset obesity in the published literature (PMID: 12499395, 18559663, 38567654); Published functional studies demonstrate a damaging effect (PMID: 17357083); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16752916, 17628007, 25332687, 18559663, 19091795, 31447099, 20826565, 34694010, 20696697, 37292813, 37953587, 37814975, 12499395, 38567654, 17357083, 24426828) (less)
|
|
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Likely pathogenic
(Oct 04, 2024)
|
criteria provided, single submitter
Method: research
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Obesity
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV005420561.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
Comment:
PS3,PM3,PM2,PP3
|
|
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Pathogenic
(May 31, 2024)
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no assertion criteria provided
Method: clinical testing
|
MC4R-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116501.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The MC4R c.896C>A variant is predicted to result in the amino acid substitution p.Pro299His. This variant has previously been reported in the heterozygous state in … (more)
The MC4R c.896C>A variant is predicted to result in the amino acid substitution p.Pro299His. This variant has previously been reported in the heterozygous state in patients who presented with morbid obesity (Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2003. PubMed ID: 12499395). This variant was also reported in the apparently homozygous state in a child who presented with severe early-onset obesity; although genetic testing was not reported for either parent, the family history was significant for obesity in both parents (Pillai et al. 2014. PubMed ID: 24426828). Furthermore, in vitro studies indicate that the p.Pro299His change results in intracellular retention of the MC4R receptor and therefore disruption of α-MSH activation (Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Roubert et al. 2010. PubMed ID: 20696697). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. In summary, we classify this variant as pathogenic. (less)
|
Comment:
Comment:
Converted during submission to Pathogenic.
Comment:
PS3, PM2
Comment:
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. Experimental studies have shown that this missense change affects MC4R function (PMID: 16083993, 16752916, 20696697, 20826565, 25332687). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 36488). This missense change has been observed in individual(s) with obesity (PMID: 12499395, 12851297, 18559663, 19091795, 24426828). This variant is present in population databases (rs52804924, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 299 of the MC4R protein (p.Pro299His).
Comment:
Observed in the apparent homozygous state and also in the heterozygous state with a second MC4R variant, phase unknown, in patients with early-onset obesity in the literature and not observed in homozygous state in controls (PMID: 34694010, 24426828, 37814975); Identified in the heterozygous state in patients with early-onset obesity in the published literature (PMID: 12499395, 18559663, 38567654); Published functional studies demonstrate a damaging effect (PMID: 17357083); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16752916, 17628007, 25332687, 18559663, 19091795, 31447099, 20826565, 34694010, 20696697, 37292813, 37953587, 37814975, 12499395, 38567654, 17357083, 24426828)
Comment:
PS3,PM3,PM2,PP3
Comment:
The MC4R c.896C>A variant is predicted to result in the amino acid substitution p.Pro299His. This variant has previously been reported in the heterozygous state in patients who presented with morbid obesity (Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2003. PubMed ID: 12499395). This variant was also reported in the apparently homozygous state in a child who presented with severe early-onset obesity; although genetic testing was not reported for either parent, the family history was significant for obesity in both parents (Pillai et al. 2014. PubMed ID: 24426828). Furthermore, in vitro studies indicate that the p.Pro299His change results in intracellular retention of the MC4R receptor and therefore disruption of α-MSH activation (Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Roubert et al. 2010. PubMed ID: 20696697). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. In summary, we classify this variant as pathogenic.
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. |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
Converted during submission to Pathogenic.
Comment:
PS3, PM2
Comment:
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. Experimental studies have shown that this missense change affects MC4R function (PMID: 16083993, 16752916, 20696697, 20826565, 25332687). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 36488). This missense change has been observed in individual(s) with obesity (PMID: 12499395, 12851297, 18559663, 19091795, 24426828). This variant is present in population databases (rs52804924, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 299 of the MC4R protein (p.Pro299His).
Comment:
Observed in the apparent homozygous state and also in the heterozygous state with a second MC4R variant, phase unknown, in patients with early-onset obesity in the literature and not observed in homozygous state in controls (PMID: 34694010, 24426828, 37814975); Identified in the heterozygous state in patients with early-onset obesity in the published literature (PMID: 12499395, 18559663, 38567654); Published functional studies demonstrate a damaging effect (PMID: 17357083); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16752916, 17628007, 25332687, 18559663, 19091795, 31447099, 20826565, 34694010, 20696697, 37292813, 37953587, 37814975, 12499395, 38567654, 17357083, 24426828)
Comment:
PS3,PM3,PM2,PP3
Comment:
The MC4R c.896C>A variant is predicted to result in the amino acid substitution p.Pro299His. This variant has previously been reported in the heterozygous state in patients who presented with morbid obesity (Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2003. PubMed ID: 12499395). This variant was also reported in the apparently homozygous state in a child who presented with severe early-onset obesity; although genetic testing was not reported for either parent, the family history was significant for obesity in both parents (Pillai et al. 2014. PubMed ID: 24426828). Furthermore, in vitro studies indicate that the p.Pro299His change results in intracellular retention of the MC4R receptor and therefore disruption of α-MSH activation (Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Roubert et al. 2010. PubMed ID: 20696697). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. In summary, we classify this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Severe obstructive sleep apnea in a child with melanocortin-4 receptor deficiency. | Pillai S | Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine | 2014 | PMID: 24426828 |
| Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. | René P | The Journal of pharmacology and experimental therapeutics | 2010 | PMID: 20826565 |
| Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. | Roubert P | The Journal of endocrinology | 2010 | PMID: 20696697 |
| 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 |
| Medical sequencing at the extremes of human body mass. | Ahituv N | American journal of human genetics | 2007 | PMID: 17357083 |
| 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 |
| Obesity-associated mutations in the human melanocortin-4 receptor gene. | MacKenzie RG | Peptides | 2006 | PMID: 16274851 |
| Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function. | Govaerts C | Peptides | 2005 | PMID: 16083993 |
| 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 |
| Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. | Lubrano-Berthelier C | Human molecular genetics | 2003 | PMID: 12499395 |
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Text-mined citations for rs52804924 ...
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 Dec 15, 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.