NM_005912.3(MC4R):c.656C>T (p.Ala219Val) AND BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 1, 2005
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:: RCV000015414.23

Allele description [Variation Report for NM_005912.3(MC4R):c.656C>T (p.Ala219Val)]

NM_005912.3(MC4R):c.656C>T (p.Ala219Val)

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.656C>T (p.Ala219Val)

HGVS:

NC_000018.10:g.60371694G>A
NG_016441.1:g.6075C>T
NM_005912.2:c.656C>T
NM_005912.3:c.656C>TMANE SELECT
NP_005903.2:p.Ala219Val
LRG_1346t1:c.656C>T
LRG_1346:g.6075C>T
LRG_1346p1:p.Ala219Val
NC_000018.9:g.58038927G>A
P32245:p.Ala219Val

Protein change:

A219V; ALA219VAL

Links:

UniProtKB: P32245#VAR_038648; OMIM: 155541.0023; dbSNP: rs121913567

NCBI 1000 Genomes Browser:

rs121913567

Molecular consequence:

NM_005912.3:c.656C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (BMIQ20)
Synonyms:: MELANOCORTIN 4 RECEPTOR DEFICIENCY; MC4R DEFICIENCY
Identifiers:: MedGen: C4759928; OMIM: 618406

Recent activity

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CdaR family protein [Clostridium perfringens]
CdaR family protein [Clostridium perfringens]
gi|2488796054|ref|WP_279324106.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035675	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2005)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15486053, 31002796

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035675

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 2005)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity.

Larsen LH, Echwald SM, Sørensen TI, Andersen T, Wulff BS, Pedersen O.

J Clin Endocrinol Metab. 2005 Jan;90(1):219-24. Epub 2004 Oct 14.

PubMed [citation]

PMID:: 15486053

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity.

Lotta LA, Mokrosiński J, Mendes de Oliveira E, Li C, Sharp SJ, Luan J, Brouwers B, Ayinampudi V, Bowker N, Kerrison N, Kaimakis V, Hoult D, Stewart ID, Wheeler E, Day FR, Perry JRB, Langenberg C, Wareham NJ, Farooqi IS.

Cell. 2019 Apr 18;177(3):597-607.e9. doi: 10.1016/j.cell.2019.03.044.

PubMed [citation]

PMID:: 31002796
PMCID:: PMC6476272

Details of each submission

From OMIM, SCV000035675.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a study of the MC4R gene in 750 Danish men with juvenile-onset obesity (BMIQ20; 618406) and 706 control subjects, Larsen et al. (2005) detected a novel missense mutation in 1 subject, ala219 to val (A219V), that arose from a 656C-T transition. The A219V variant showed significant impairment of cAMP-induced activity in response to melanotan II (MTII) compared with the wildtype receptor (34%).

In time-resolved assays quantifying cAMP production and beta-arrestin-2 (ARBB2; 107941) recruitment, Lotta et al. (2019) observed loss-of-function effects with the A219V mutant in the cAMP assay, whereas the mutant showed similar effects to wildtype MC4R in the beta-arrestin-mediated signaling assay.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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