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

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 22, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000332082.8

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
Synonyms:: Obesity disorder
Identifiers:: MONDO: MONDO:0011122; MeSH: D009765; MedGen: C0028754; Orphanet: 71529; Human Phenotype Ontology: HP:0001513

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000409977	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15448103, 12588803, 12690102, 10903343, 25332687, 12646665, 17628007, 15486053 Citation Link,
SCV001423086	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (9) [See all records that cite these PMIDs] 12588803, 15486053, 12690102, 26788538, 15448103, 29861388, 12646665, 20826565, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000409977

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Apr 28, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001423086

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2020)

germline

curation

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.

Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S.

J Clin Invest. 2000 Jul;106(2):271-9.

PubMed [citation]

PMID:: 10903343
PMCID:: PMC314308

Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene.

He S, Tao YX.

Int J Biol Sci. 2014;10(10):1128-37. doi: 10.7150/ijbs.10359.

PubMed [citation]

PMID:: 25332687
PMCID:: PMC4202029

See all PubMed Citations (12)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000409977.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The MC4R c.494G>A (p.Arg165Gln) variant has been reported in at least four studies in a heterozygous state in a total of 18 individuals with severe early-onset obesity, severe obesity, or juvenile onset obesity (Farooqi et al. 2000; Farooqi et al. 2003; Ma et al. 2004; Larsen et al. 2005). In one family, the p.Arg165Gln variant was detected in both the affected father and affected son. The p.Arg165Gln variant was absent from 2,070 control alleles but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the p.Arg165Gln variant was expressed but defective in trafficking to the cell surface and was retained intracellularly. The variant was also shown to have impaired ligand-stimulated ERK 1/2 activation, a partial cAMP response when stimulated with alpha-MSH, and to exhibit a 17-fold decrease in affinity to NDP-MSH as a result of a markedly reduced ligand binding capacity (Nijenhuis et al. 2003; Yeo et al. 2003; He et al. 2014). The Arg165 residue is conserved across thirty species (Staubert et al. 2007). Based on the evidence, the p.Arg165Gln variant is classified as pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423086.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (9)

Description

The p.Arg165Gln variant in MC4R has been reported in 20 individuals with Obesity, segregated with disease in 2 affected relatives from one family, (PMID: 10903343, 12646665, 15448103, 15486053, 29861388), and has been identified in 0.005441% (1/18380) of East Asian chromosomes and 0.004399% (5/113650) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747681609). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact expression, ligand binding, and protein activity (PMID: 12588803, 12690102, 12646665, 15486053, 20826565). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg165Gly, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22106157, 24276017, 25332687). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM2_Supporting, PM5_supporting (Richards 2015).

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

Last Updated: Jun 9, 2024

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