NM_005912.2(MC4R):c.110A>T (p.Asp37Val) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 16, 2023
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:: RCV001699179.3

Allele description [Variation Report for NM_005912.2(MC4R):c.110A>T (p.Asp37Val)]

NM_005912.2(MC4R):c.110A>T (p.Asp37Val)

Gene:

MC4R:melanocortin 4 receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.32

Genomic location:

Preferred name:

NM_005912.2(MC4R):c.110A>T (p.Asp37Val)

HGVS:

NC_000018.10:g.60372240T>A
NG_016441.1:g.5529A>T
NM_005912.3:c.110A>TMANE SELECT
NP_005903.2:p.Asp37Val
LRG_1346t1:c.110A>T
LRG_1346:g.5529A>T
LRG_1346p1:p.Asp37Val
NC_000018.9:g.58039473T>A
NM_005912.2:c.110A>T
P32245:p.Asp37Val

Protein change:

D37V; ASP37VAL

Links:

UniProtKB: P32245#VAR_010705; OMIM: 155541.0003; OMIM: 155541.0004; dbSNP: rs13447325

NCBI 1000 Genomes Browser:

rs13447325

Molecular consequence:

NM_005912.3:c.110A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001924585	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001926982	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV004297610	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12970296, 16752916, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001924585

Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Likely benign

germline

clinical testing

SCV001926982

Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Likely benign

germline

clinical testing

SCV004297610

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 16, 2023)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity.

Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, Brokamp B, Goldschmidt H, Siegfried W, Remschmidt H, Schäfer H, Gudermann T, Hebebrand J.

J Clin Endocrinol Metab. 2003 Sep;88(9):4258-67.

PubMed [citation]

PMID:: 12970296

Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist.

Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, Shaw AM, Millard WJ, Haskell-Luevano C.

Biochemistry. 2006 Jun 13;45(23):7277-88.

PubMed [citation]

PMID:: 16752916

See all PubMed Citations (3)

Details of each submission

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924585.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001926982.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Invitae, SCV004297610.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 37 of the MC4R protein (p.Asp37Val). This variant is present in population databases (rs13447325, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features associated with MC4R-related obesity (PMID: 12970296). ClinVar contains an entry for this variant (Variation ID: 14319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MC4R function (PMID: 16752916). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Aug 25, 2024

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