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NM_005912.3(MC4R):c.910C>T (p.Leu304Phe) AND MC4R-related disorder

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 30, 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:
RCV003934219.2

Allele description [Variation Report for NM_005912.3(MC4R):c.910C>T (p.Leu304Phe)]

NM_005912.3(MC4R):c.910C>T (p.Leu304Phe)

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.910C>T (p.Leu304Phe)
HGVS:
  • NC_000018.10:g.60371440G>A
  • NG_016441.1:g.6329C>T
  • NM_005912.3:c.910C>TMANE SELECT
  • NP_005903.2:p.Leu304Phe
  • LRG_1346t1:c.910C>T
  • LRG_1346:g.6329C>T
  • LRG_1346p1:p.Leu304Phe
  • NC_000018.9:g.58038673G>A
  • NM_005912.2:c.910C>T
Protein change:
L304F
Molecular consequence:
  • NM_005912.3:c.910C>T - 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
SCV004754896PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Uncertain significance
(May 30, 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, SCV004754896.2

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

Description

The MC4R c.910C>T variant is predicted to result in the amino acid substitution p.Leu304Phe. This variant has been reported in the heterozygous state in individuals with obesity (van den Berg et al. 2011. PubMed ID: 20966905; Thearle et al. 2011. PubMed ID: 22106157). Functional studies analyzing NDP-MSH receptor binding in HEK cells showed that this variant decreased expression levels to ~40% of wild receptor expression and cell surface expression and retainment in the ER was decreased as compared to wildtype (van den Berg et al. 2011. PubMed ID: 20966905); however another study showed p.Leu304Phe had no impact on MC4R function (Thearle et al. 2011. PubMed ID: 22106157). In addition, affinity for NDP-MSH and receptor activation was not significantly altered as compared to wildtype (van den Berg et al. 2011. PubMed ID: 20966905). Another study analyzing signaling preference for gain-of-function MC4R variants determined that the p.Leu304Phe variant had no evidence of biased signaling (Lotta et al. 2019. PubMed ID: 31002796). This variant is reported in 0.034% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Last Updated: Oct 13, 2024