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NM_005912.3(MC4R):c.494G>A (p.Arg165Gln) AND Obesity due to melanocortin 4 receptor deficiency

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 26, 2018
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004017591.1

Allele description [Variation Report for NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)]

NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)

Gene:
MC4R:melanocortin 4 receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.32
Genomic location:
Preferred name:
NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)
HGVS:
  • NC_000018.10:g.60371856C>T
  • NG_016441.1:g.5913G>A
  • NM_005912.2(MC4R):c.494G>A
  • NM_005912.3:c.494G>AMANE SELECT
  • NP_005903.2:p.Arg165Gln
  • LRG_1346t1:c.494G>A
  • LRG_1346:g.5913G>A
  • LRG_1346p1:p.Arg165Gln
  • NC_000018.9:g.58039089C>T
  • NC_000018.9:g.58039089C>T
  • NM_005912.2(MC4R):c.494G>A
  • NM_005912.2:c.494G>A
  • NM_005912.3:c.494G>A
  • P32245:p.Arg165Gln
Protein change:
R165Q
Links:
UniProtKB: P32245#VAR_038644; dbSNP: rs747681609
NCBI 1000 Genomes Browser:
rs747681609
Molecular consequence:
  • NM_005912.3:c.494G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Obesity due to melanocortin 4 receptor deficiency
Identifiers:
MONDO: MONDO:0019115; MedGen: C4273958

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004848248Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Sep 26, 2018) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity.

Nijenhuis WA, Garner KM, van Rozen RJ, Adan RA.

J Biol Chem. 2003 Jun 20;278(25):22939-45. Epub 2003 Apr 9.

PubMed [citation]
PMID:
12690102

Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.

Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S.

N Engl J Med. 2003 Mar 20;348(12):1085-95.

PubMed [citation]
PMID:
12646665
See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848248.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

The p.Arg165Gln variant in MC4R has been reported in >15 individuals with severe obesity and segregated with disease in one affected relative (Farooqi 2003, Ma 2004, Larsen 2005). This variant has been identified in 6/111582 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact protein function (Nijenhuis 2003, Farooqi 2003, Larsen 2005, Xiang 2006, Thearle 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg165Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg165Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_Supporting, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024