ClinVar Genomic variation as it relates to human health
NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002303.6(LEPR):c.668A>G (p.Gln223Arg)
Variation ID: 8521 Accession: VCV000008521.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p31.3 1: 65592830 (GRCh38) [ NCBI UCSC ] 1: 66058513 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 9, 2016 Sep 29, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002303.6:c.668A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
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 - Protein change
- Q223R
- Other names
- -
- Canonical SPDI
- NC_000001.11:65592829:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.41574 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.49417
The Genome Aggregation Database (gnomAD) 0.50085
The Genome Aggregation Database (gnomAD), exomes 0.50598
Exome Aggregation Consortium (ExAC) 0.51031
1000 Genomes Project 30x 0.57823
1000 Genomes Project 0.58427
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 | ||
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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. |
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LEPR | - | - |
GRCh38 GRCh37 |
431 | 489 |
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. |
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LEPTIN RECEPTOR POLYMORPHISM
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Benign (1) |
no assertion criteria provided
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Nov 1, 2007 | RCV000009047.3 |
Benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000348520.5 | |
Benign (3) |
criteria provided, single submitter
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Jul 26, 2017 | RCV000518727.4 | |
Benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000281795.5 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001668124.8 |
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. |
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Benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Leptin Receptor Deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000358804.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Monogenic Non-Syndromic Obesity
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000358803.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Benign
(Jul 26, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000614013.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Benign
(Aug 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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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)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002416578.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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Benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005287382.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Benign
(Nov 01, 2007)
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no assertion criteria provided
Method: literature only
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LEPTIN RECEPTOR POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029264.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 09, 2016 |
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)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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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 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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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 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.