VCV000014328.3 - ClinVar

NM_005912.3(MC4R):c.374_375inv (p.Ile125Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005912.3(MC4R):c.374_375inv (p.Ile125Lys)

Variation ID: 14328 Accession: VCV000014328.3

Type and length

Inversion, 2 bp

Location

Cytogenetic: 18q21.32 18: 60371975-60371976 (GRCh38) [ NCBI UCSC ] 18: 58039208-58039209 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 18, 2017	Oct 8, 2024	Feb 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005912.3:c.374_375inv MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005903.2:p.Ile125Lys	missense
NM_005912.2:c.374_375delinsAA
NC_000018.10:g.60371975_60371976inv
NC_000018.9:g.58039208_58039209inv
NG_016441.1:g.5793_5794inv
LRG_1346:g.5793_5794inv
LRG_1346t1:c.374_375inv	LRG_1346p1:p.Ile125Lys

... more HGVS ... less HGVS

Protein change

Other names

I125K

Canonical SPDI

NC_000018.10:60371974:AA:TT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

LOVD 3: MC4R_000208 OMIM: 155541.0013 VarSome

Comment on variant

NCBI staff provided an HGVS expression for allelic variant 155541.0013 to be consistent with the record in https://databases.lovd.nl/shared/genes/MC4R. Staff could not identify a publication verifying the nucleotide change.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MC4R		-	-	GRCh38 GRCh37	235	309

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Pathogenic (1)	no assertion criteria provided	Mar 20, 2003	RCV000015404.27
MC4R-related disorder	Likely pathogenic (1)	no assertion criteria provided	Feb 21, 2024	RCV004748522.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 20, 2003)	no assertion criteria provided Method: literature only	OBESITY (BMIQ20) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035665.3 First in ClinVar: Apr 04, 2013 Last updated: May 06, 2019	Publications: PubMed (2) PubMed: 12646665‚ 12588803 Comment on evidence: In each of 2 presumably unrelated families, Farooqi et al. (2003) found that a parent and 1 child with early-onset obesity (BMIQ20; 618406) were heterozygous … (more) In each of 2 presumably unrelated families, Farooqi et al. (2003) found that a parent and 1 child with early-onset obesity (BMIQ20; 618406) were heterozygous for an ile125-to-lys (I125K) mutation in the MC4R gene. The protein showed no activity on in vitro assay. Yeo et al. (2003) demonstrated that the I125K mutation was completely unable to generate cAMP in response to ligand. (less)
Likely pathogenic (Feb 21, 2024)	no assertion criteria provided Method: clinical testing	MC4R-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005359687.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MC4R c.374_375delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in the heterozygous state in at least … (more) The MC4R c.374_375delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in the heterozygous state in at least two families segregating with obesity (Yeo et al. 2003. PubMed ID: 12588803; family 5 and family 6, Farooqi et al. 2003. PubMed ID: 12646665). Functional studies including pharmacological rescue experiments showed that this variant reduced ligand-stimulated cyclic AMP (cAMP) response (Farooqi et al. 2003. PubMed ID: 12646665; René et al. 2010. PubMed ID: 20826565; He et al. 2014. PubMed ID: 25332687). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. (less)

Comment:

The MC4R c.374_375delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in the heterozygous state in at least two families segregating with obesity (Yeo et al. 2003. PubMed ID: 12588803; family 5 and family 6, Farooqi et al. 2003. PubMed ID: 12646665). Functional studies including pharmacological rescue experiments showed that this variant reduced ligand-stimulated cyclic AMP (cAMP) response (Farooqi et al. 2003. PubMed ID: 12646665; René et al. 2010. PubMed ID: 20826565; He et al. 2014. PubMed ID: 25332687). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.	Farooqi IS	The New England journal of medicine	2003	PMID: 12646665
Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.	Yeo GS	Human molecular genetics	2003	PMID: 12588803

Text-mined citations for this variant ...

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_005912.3(MC4R):c.374_375inv (p.Ile125Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...