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NM_005912.3(MC4R):c.173G>A (p.Ser58Asn) AND MC4R-related disorder

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 24, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004748268.1

Allele description [Variation Report for NM_005912.3(MC4R):c.173G>A (p.Ser58Asn)]

NM_005912.3(MC4R):c.173G>A (p.Ser58Asn)

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.173G>A (p.Ser58Asn)
HGVS:
  • NC_000018.10:g.60372177C>T
  • NG_016441.1:g.5592G>A
  • NM_005912.3:c.173G>AMANE SELECT
  • NP_005903.2:p.Ser58Asn
  • LRG_1346t1:c.173G>A
  • LRG_1346:g.5592G>A
  • LRG_1346p1:p.Ser58Asn
  • NC_000018.9:g.58039410C>T
  • NM_005912.2:c.173G>A
Protein change:
S58N
Molecular consequence:
  • NM_005912.3:c.173G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
MC4R-related disorder
Synonyms:
MC4R-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005349642PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Likely pathogenic
(Sep 24, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005349642.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The MC4R c.173G>A variant is predicted to result in the amino acid substitution p.Ser58Asn. This variant was reported in a presumably healthy individual in a study of obese individuals (Kirac et al 2016. PubMed ID 27634552). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. At PreventionGenetics, we have observed this variant in eight individuals with obesity and segregation in a parent and child with obesity (internal data). An alternative nucleotide change affecting the same amino acid residue, c.172A>T (p.Ser58Cys), has been reported in association with obesity, but was also observed in controls (Dubern et al. 2001. PubMed ID: 11487744; Yurtcu et al. 2009. PubMed ID: 19184404). Functional studies indicate that the p.Ser58Cys change results in defective trafficking to the cell surface and decreased ligand binding in vitro (see for example Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Tao and Segaloff. 2003. PubMed ID: 12959994; He and Tao. 2014. PubMed ID: 25332687), suggesting that the p.Ser58 residue is critical for MC4R function. This variant is interpreted as likely pathogenic for autosomal dominant MC4R-related disorders.

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

Last Updated: Nov 10, 2024