LEPR

leptin receptor, the group of CD molecules|Immunoglobulin like domain containing

Basic information

Region (hg38): 1:65420652-65641559

Links

ENSG00000116678 ∙ NCBI:3953 ∙ OMIM:601007 ∙ HGNC:6554 ∙ Uniprot:P48357 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• obesity due to leptin receptor gene deficiency (Strong), mode of inheritance: AR
• obesity due to leptin receptor gene deficiency (Strong), mode of inheritance: AR
• obesity due to leptin receptor gene deficiency (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leptin receptor deficiency	AR	Allergy/Immunology/Infectious; Endocrine	In addition to endocrine manifestations, individuals may be susceptible to infections (eg, respiratory infections), which, coupled with other manifestations (eg, severe obesity) can have severe sequelae such that prophylaxis and rapid treatment may be beneficial; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial	Allergy/Immunology/Infectious; Endocrine	8666155; 9537324; 17229951; 21306929; 23275530; 23616257; 35528826
Standard treatments for obesity, such as gastric surgery, have been described as beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LEPR gene.

• not provided (5 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LEPR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	40	2	49
missense		2	100	9	3	114
nonsense	3	1				4
start loss						0
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)		2	1			3
splice region			2	3	1	6
non coding			20	34	44	98
Total	5	6	128	83	49

Highest pathogenic variant AF is 0.0000263

Variants in LEPR

This is a list of pathogenic ClinVar variants found in the LEPR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-65420675-C-A		Obesity due to leptin receptor gene deficiency	Uncertain significance (Jan 13, 2018)
1-65420676-C-T		Monogenic Non-Syndromic Obesity • Obesity due to leptin receptor gene deficiency	Uncertain significance (Jan 12, 2018)
1-65420715-T-C		Obesity due to leptin receptor gene deficiency • Monogenic Non-Syndromic Obesity	Benign (Jun 14, 2016)
1-65420717-C-T		Monogenic Non-Syndromic Obesity • Obesity due to leptin receptor gene deficiency	Uncertain significance (Jun 14, 2016)
1-65421440-G-A			Likely benign (Jun 02, 2018)
1-65425307-C-T		Obesity due to leptin receptor gene deficiency • Monogenic Non-Syndromic Obesity	Conflicting classifications of pathogenicity (May 20, 2021)
1-65425308-G-A		not specified	Uncertain significance (Nov 10, 2022)
1-65425348-T-G		Obesity due to leptin receptor gene deficiency	Uncertain significance (Jan 13, 2018)
1-65425500-T-A			Benign (May 21, 2021)
1-65429863-G-A		not specified	Uncertain significance (Oct 22, 2021)
1-65429881-G-A		not specified	Uncertain significance (Apr 23, 2024)
1-65429968-C-T		not specified	Uncertain significance (Jun 21, 2023)
1-65429999-T-C		not specified	Uncertain significance (Sep 14, 2022)
1-65565380-G-A			Benign (Aug 09, 2018)
1-65565531-A-T		Obesity due to leptin receptor gene deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jun 14, 2016)
1-65565561-G-C		LEPR-related disorder	Likely benign (Aug 23, 2023)
1-65565568-G-A		LEPR-related disorder	Likely pathogenic (Jul 02, 2024)
1-65565577-A-G		LEPR-related disorder	Likely benign (Sep 13, 2022)
1-65565591-T-C		LEPR-related disorder	Uncertain significance (May 16, 2024)
1-65565598-A-G		LEPR-related disorder	Likely benign (Apr 18, 2024)
1-65565601-T-C		Obesity due to leptin receptor gene deficiency • not specified • LEPR-related disorder	Conflicting classifications of pathogenicity (Jan 11, 2024)
1-65565843-TCTCA-T			Likely benign (Oct 29, 2019)
1-65565843-T-TCA			Likely benign (Aug 21, 2019)
1-65565843-T-TCACA			Benign (Aug 06, 2019)
1-65565843-T-TCACACA			Likely benign (Aug 10, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LEPR	protein_coding	protein_coding	ENST00000349533	18	220995

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.995	0.00525	125718	0	28	125746	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.42	490	587	0.835	0.0000275	7702
Missense in Polyphen		88	133.57	0.65885		1797
Synonymous	0.266	204	209	0.977	0.0000103	2122
Loss of Function	5.77	9	55.3	0.163	0.00000242	755

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000272	0.000272
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000124	0.000123
Middle Eastern	0.000109	0.000109
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (By similarity) (PubMed:9537324). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:25060689, PubMed:12504075, PubMed:8805376). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter- regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production (By similarity). {ECO:0000250|UniProtKB:P48356, ECO:0000269|PubMed:12504075, ECO:0000269|PubMed:22405007, ECO:0000269|PubMed:25060689, ECO:0000269|PubMed:8805376, ECO:0000269|PubMed:9537324, ECO:0000305|PubMed:25232147}.; FUNCTION: Isoform E: Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis. {ECO:0000250|UniProtKB:P48356}.
• Disease: DISEASE: Leptin receptor deficiency (LEPRD) [MIM:614963]: A rare disease characterized by normal levels of serum leptin, hyperphagia and severe obesity from an early age. Additional features include alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. {ECO:0000269|PubMed:25751111, ECO:0000269|PubMed:9537324}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Adipocytokine signaling pathway - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);JAK-STAT-Core;AMP-activated Protein Kinase (AMPK) Signaling;Leptin signaling pathway;JAK-STAT;Leptin and adiponectin;Leptin Insulin Overlap;Signal Transduction;reversal of insulin resistance by leptin;JAK STAT MolecularVariation 1;JAK STAT MolecularVariation 2;JAK STAT pathway and regulation;Signaling by Leptin;Leptin;Signaling events mediated by PTP1B (Consensus)

Recessive Scores

• pRec: 0.0824

Intolerance Scores

• loftool: 0.609
• rvis_EVS: -0.22
• rvis_percentile_EVS: 37.7

Haploinsufficiency Scores

• pHI: 0.553
• hipred: Y
• hipred_score: 0.617
• ghis: 0.473

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.964

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Lepr
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); reproductive system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; neoplasm

Zebrafish Information Network

• Gene name: lepr
• Affected structure: secondary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: branchiness

Gene ontology

• Biological process: angiogenesis;energy reserve metabolic process;phagocytosis;cell surface receptor signaling pathway;multicellular organism development;cholesterol metabolic process;negative regulation of autophagy;sexual reproduction;T cell differentiation;leptin-mediated signaling pathway;glucose homeostasis;response to leptin;negative regulation of gluconeogenesis;regulation of bone remodeling;negative regulation of hydrolase activity;regulation of feeding behavior;energy homeostasis;bone growth;positive regulation of cold-induced thermogenesis
• Cellular component: extracellular region;external side of plasma membrane;integral component of membrane;basolateral plasma membrane;receptor complex
• Molecular function: transmembrane signaling receptor activity;cytokine receptor activity;protein binding;peptide hormone binding;cytokine binding;leptin receptor activity;identical protein binding