VCV000008521.11 - ClinVar

NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)

Interpretation:: Benign
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 8
First in ClinVar:: Mar 9, 2016
Most recent Submission:: Feb 7, 2023
Last evaluated:: Nov 1, 2022
Accession:: VCV000008521.11
Variation ID:: 8521
Description:: single nucleotide variant

NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)

Allele ID

23560

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

1p31.3

Genomic location

1: 65592830 (GRCh38) GRCh38 UCSC

1: 66058513 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_002303.6:c.668A>G MANE Select	NP_002294.2:p.Gln223Arg	missense
NM_001003679.3:c.668A>G	NP_001003679.1:p.Gln223Arg	missense
NM_001003680.3:c.668A>G	NP_001003680.1:p.Gln223Arg	missense
NM_001198687.2:c.668A>G	NP_001185616.1:p.Gln223Arg	missense
NM_001198688.1:c.668A>G	NP_001185617.1:p.Gln223Arg	missense
NM_001198689.2:c.668A>G	NP_001185618.1:p.Gln223Arg	missense
NC_000001.11:g.65592830A>G
NC_000001.10:g.66058513A>G
NG_015831.2:g.177266A>G
LRG_283:g.177266A>G
LRG_283t1:c.668A>G	LRG_283p1:p.Gln223Arg
LRG_283t2:c.668A>G	LRG_283p2:p.Gln223Arg
LRG_283t3:c.668A>G	LRG_283p3:p.Gln223Arg
LRG_283t4:c.668A>G	LRG_283p4:p.Gln223Arg
	P48357:p.Gln223Arg

... more HGVS ... less HGVS

Protein change

Q223R

Other names

Canonical SPDI

NC_000001.11:65592829:A:G

Functional consequence

Global minor allele frequency (GMAF)

0.41574 (A)

Allele frequency

Trans-Omics for Precision Medicine (TOPMed) 0.50518

Exome Aggregation Consortium (ExAC) 0.51031

1000 Genomes Project 0.58427

The Genome Aggregation Database (gnomAD), exomes 0.50598

The Genome Aggregation Database (gnomAD) 0.50085

The Genome Aggregation Database (gnomAD) 0.53239

Trans-Omics for Precision Medicine (TOPMed) 0.49417

Links

ClinGen: CA119663

UniProtKB: P48357#VAR_002705

OMIM: 601007.0001

dbSNP: rs1137101

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not provided	Benign	2	criteria provided, multiple submitters, no conflicts	Nov 1, 2022	RCV001668124.6
Monogenic Non-Syndromic Obesity	Benign	1	criteria provided, single submitter	Jun 14, 2016	RCV000281795.4
Obesity due to leptin receptor gene deficiency	Benign	1	criteria provided, single submitter	Jun 14, 2016	RCV000348520.4
not specified	Benign	3	criteria provided, single submitter	Jul 26, 2017	RCV000518727.3
LEPTIN RECEPTOR POLYMORPHISM	Benign	1	no assertion criteria provided	Nov 1, 2007	RCV000009047.3

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
LEPR		-	-	GRCh38 GRCh37	200	256

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Leptin Receptor Deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000358804.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 11354636
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Monogenic Non-Syndromic Obesity Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000358803.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 11354636
Benign (Jul 26, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Inc Accession: SCV000614013.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017
Benign (Aug 09, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001890175.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 9175732, 26150085, 24985001, 32429577, 24051404, 23954230, 23429533, 12634434, 28386678, 22333091, 25114924, 24631298, 11354636, 24146750, 24743494, 21233812, … (more) This variant is associated with the following publications: (PMID: 9175732, 26150085, 24985001, 32429577, 24051404, 23954230, 23429533, 12634434, 28386678, 22333091, 25114924, 24631298, 11354636, 24146750, 24743494, 21233812, 18997673, 20874424, 19344216, 21698367, 25516614, 18204169, 22127368, 18855010, 21393862, 21207066, 20183928, 22734460, 23769971, 19017403, 21159927, 23026206, 23966608, 19427969) (less)
Benign (Nov 01, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Invitae Accession: SCV002416578.2 First in ClinVar: Apr 08, 2022 Last updated: Feb 07, 2023
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925214.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929986.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Nov 01, 2007)	no assertion criteria provided Method: literature only	LEPTIN RECEPTOR POLYMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029264.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 09, 2016	Publications: PubMed (6) PubMed: 8666155‚ 11354636‚ 11443193‚ 17785359‚ 21393862‚ 22331430 Thompson, D. B., Norman, R. A., (more...) Thompson, D. B., Norman, R. A., Ravussin, E., Knowler, W. C., Bennett, P., Bogardus, C. Association of the GLN223ARG polymorphism in the leptin receptor gene with plasma leptin levels, insulin secretion and NIDDM in Pima Indians. (Abstract) Diabetologia 40: A177, 1997. Comment on evidence: In hypothalamic tissue from lean and obese humans obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office, Considine et al. (1996) detected an … (more) In hypothalamic tissue from lean and obese humans obtained shortly after autopsy in the Washington, D.C. Medical Examiner's Office, Considine et al. (1996) detected an A-to-G sequence polymorphism at nucleotide 668 of the leptin receptor cDNA. This base substitution changed a glutamine to an arginine at position 23 of the leptin receptor protein. Of 15 subjects analyzed, 11 were heterozygous for this base change and 3 were homozygous. There was no difference in the amount of leptin-receptor mRNA in 7 lean and 8 obese subjects as determined by RT-PCR. The occurrence of the polymorphic allele(s) did not correlate with the body mass index in the patients studied. The results suggested that leptin resistance observed in obese humans is not due to a defect in the leptin receptor. An A/G single-nucleotide polymorphism in the LEPR gene is associated with a gln223-to-arg (Q223R) amino acid polymorphism. Thompson et al. (1997) found that homozygosity for the G allele is associated with lower plasma leptin levels after correction for obesity, gender, and family. Quinton et al. (2001) sought to determine whether similar associations could be observed in Caucasians by studying a community-based population of postmenopausal women in the Sheffield area of the U.K. They found that genotypes at that locus are associated with differences in body mass index, fat mass, and serum leptin levels. Measurement of serum leptin-binding activity indicated that this may reflect changed receptor function associated with genotype. In a group of postmenopausal women with impaired glucose tolerance, Wauters et al. (2001) found an association of the Q223R polymorphism with insulin response to an oral glucose tolerance test. Richert et al. (2007) investigated the association of the Q223R polymorphism in the LEPR gene with bone mineral content and areal bone mineral density in prepubertal boys. LEPR genotypes were significantly associated with baseline bone mineral content at the hip (p = 0.017), femur diaphysis (p = 0.019), and radius (p = 0.007), and with height (p = 0.041) as well as with physical activity (p = 0.016). On average, bone mineral content was 8 to 12% lower in arg/arg than in gln/gln carriers, with gln/arg carriers having intermediate values. Associations with height and bone mineral content at femur diaphysis and radius remained significant after 2 years. Significant differences in 2-year bone mass gain at the spine and femur neck were also found among LEPR genotypes. Richert et al. (2007) concluded that the LEPR Q223R polymorphism was associated with bone mass in growing boys. The association, however, was markedly dependent on bone area, body size, and physical activity, in addition to VDR genetic variation, suggesting that the leptin system may modulate bone mass in humans mostly through indirect mechanisms. Amebiasis, a potentially fatal enteric infection caused by the parasite Entamoeba histolytica, is exacerbated by malnutrition. Duggal et al. (2011) prospectively observed a cohort of Bangladeshi children for 9 years beginning at preschool age for E. histolytica infection and evaluated them for LEPR variants. They found that children carrying the 223R allele of the Q223R polymorphism had 4-fold increased susceptibility to intestinal infection compared with those homozygous for 223Q. Examination of an independent cohort of adult patients showed that those carrying the 223R allele had increased risk of amebic liver abscess. Mice with at least 1 copy of the R allele were more susceptible to amebic infection and exhibited greater levels of mucosal destruction, as well as intestinal epithelial apoptosis, after infection. Duggal et al. (2011) proposed that leptin signaling is important in mucosal defense against amebiasis and that LPR polymorphisms explain differences in susceptibility of children to amebiasis. Using human cells, Marie et al. (2012) showed that the Q223R polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 (102582) activation. (less)

Comment:

This variant is associated with the following publications: (PMID: 9175732, 26150085, 24985001, 32429577, 24051404, 23954230, 23429533, 12634434, 28386678, 22333091, 25114924, 24631298, 11354636, 24146750, 24743494, 21233812, 18997673, 20874424, 19344216, 21698367, 25516614, 18204169, 22127368, 18855010, 21393862, 21207066, 20183928, 22734460, 23769971, 19017403, 21159927, 23026206, 23966608, 19427969)

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 this variant

Title	Author	Journal	Year	Link
Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.	Marie CS	Infection and immunity	2012	PMID: 22331430
A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children.	Duggal P	The Journal of clinical investigation	2011	PMID: 21393862
Bone mass in prepubertal boys is associated with a Gln223Arg amino acid substitution in the leptin receptor.	Richert L	The Journal of clinical endocrinology and metabolism	2007	PMID: 17785359
Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance.	Wauters M	The Journal of clinical endocrinology and metabolism	2001	PMID: 11443193
A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women.	Quinton ND	Human genetics	2001	PMID: 11354636
The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations.	Considine RV	Diabetes	1996	PMID: 8666155
Thompson, D. B., Norman, R. A., Ravussin, E., Knowler, W. C., Bennett, P., Bogardus, C. Association of the GLN223ARG polymorphism in the leptin receptor gene with plasma leptin levels, insulin secretion and NIDDM in Pima Indians. (Abstract) Diabetologia 40: A177, 1997.	-	-	-	-

Text-mined citations for rs1137101...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 05, 2023

ClinVar Genomic variation as it relates to human health

NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)

NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs1137101...