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NM_005912.3(MC4R):c.185A>G (p.Asn62Ser) AND Obesity due to melanocortin 4 receptor deficiency

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 28, 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:
RCV004017251.1

Allele description [Variation Report for NM_005912.3(MC4R):c.185A>G (p.Asn62Ser)]

NM_005912.3(MC4R):c.185A>G (p.Asn62Ser)

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.185A>G (p.Asn62Ser)
HGVS:
  • NC_000018.10:g.60372165T>C
  • NG_016441.1:g.5604A>G
  • NM_005912.3:c.185A>GMANE SELECT
  • NP_005903.2:p.Asn62Ser
  • LRG_1346t1:c.185A>G
  • LRG_1346:g.5604A>G
  • LRG_1346p1:p.Asn62Ser
  • NC_000018.9:g.58039398T>C
  • P32245:p.Asn62Ser
Protein change:
N62S; ASN62SER
Links:
UniProtKB: P32245#VAR_038636; OMIM: 155541.0019; dbSNP: rs121913566
NCBI 1000 Genomes Browser:
rs121913566
Molecular consequence:
  • NM_005912.3:c.185A>G - 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
SCV004848250Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Sep 28, 2018) 		germlineclinical testing

PubMed (5)
[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

Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.

Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O'Rahilly S.

Hum Mol Genet. 2003 Mar 1;12(5):561-74.

PubMed [citation]
PMID:
12588803

Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity.

Tao YX, Segaloff DL.

Endocrinology. 2003 Oct;144(10):4544-51. Epub 2003 Jun 19.

PubMed [citation]
PMID:
12959994
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848250.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.Asn62Ser variant in MC4R has been reported in the homozygous state in 1 individual with severe obesity, and segregated with disease in 4 homozygous and 4 heterozygous affected relatives (Farooqi 2003, Farooqi 2003). Of note, the homozygous individuals in this family were more severely affected than the heterozygous individuals. This variant has been identified in 1/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Asn62Ser variant may impact protein function (Tao 2003, Yeo 2003); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Asn62Ser 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.Asn62Ser variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PP3, PS3_Supporting.

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

Last Updated: May 7, 2024