LEP

leptin, the group of Neuropeptides

Basic information

Region (hg38): 7:128241277-128257629

Previous symbols: [ "OBS", "OB" ]

Links

ENSG00000174697 ∙ NCBI:3952 ∙ OMIM:164160 ∙ HGNC:6553 ∙ Uniprot:P41159 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leptin deficiency or dysfunction	AR	Endocrine	Severely affected individuals may benefit from treatment with leptin	Endocrine	9202122; 9745435; 9500540; 10486419; 11281277; 11689931; 15070752; 17986612; 17206122; 19427251; 20382689; 22463805
Heterozygotes may display milder forms of disease

ClinVar

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

• Obesity due to congenital leptin deficiency (75 variants)
• Monogenic Non-Syndromic Obesity (43 variants)
• not provided (27 variants)
• LEP-related condition (5 variants)
• not specified (3 variants)
• Leptin dysfunction (2 variants)
• Monogenic diabetes (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LEP 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	2	9
missense	2	2	11	1		16
nonsense	1					1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			54	11	5	70
Total	3	2	65	19	7

Highest pathogenic variant AF is 0.0000263

Variants in LEP

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

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

Position	Type	Phenotype	Significance	ClinVar
7-128241296-G-A		Obesity due to congenital leptin deficiency • Monogenic Non-Syndromic Obesity	Benign/Likely benign (Dec 21, 2020)
7-128252005-T-G		Obesity due to congenital leptin deficiency	Uncertain significance (Jan 13, 2018)
7-128252033-C-G		not specified	Likely benign (Sep 12, 2018)
7-128252039-C-T		Obesity due to congenital leptin deficiency • Monogenic Non-Syndromic Obesity • LEP-related disorder	Conflicting classifications of pathogenicity (Jan 29, 2024)
7-128252040-G-A		LEP-related disorder	Uncertain significance (Sep 26, 2023)
7-128252042-A-G			Likely benign (Mar 04, 2022)
7-128252048-G-C		LEP-related disorder	Uncertain significance (Sep 26, 2023)
7-128252063-T-C			Likely benign (Aug 22, 2022)
7-128252071-A-G		LEP-related disorder • Obesity due to congenital leptin deficiency	Conflicting classifications of pathogenicity (Jun 21, 2022)
7-128252091-C-T			Pathogenic (Nov 08, 2017)
7-128252093-A-G			Benign/Likely benign (Jan 29, 2024)
7-128252150-C-T		LEP-related disorder	Likely benign (Jul 09, 2019)
7-128252151-A-G		LEP-related disorder	Uncertain significance (Dec 05, 2023)
7-128252161-C-T		Obesity due to congenital leptin deficiency	Uncertain significance (Jan 12, 2018)
7-128252168-GAGAGTATGCGGGGACAAAGT-G			Likely benign (Jun 30, 2023)
7-128252177-C-T		Obesity due to congenital leptin deficiency • Monogenic Non-Syndromic Obesity	Uncertain significance (Jun 14, 2016)
7-128254187-G-A			Benign (Sep 22, 2018)
7-128254195-G-T			Likely benign (Feb 03, 2020)
7-128254252-G-A			Benign (Apr 07, 2019)
7-128254288-G-C			Likely benign (Jun 27, 2019)
7-128254297-G-A			Benign (Apr 24, 2019)
7-128254354-C-T			Benign (Jan 16, 2019)
7-128254424-G-A		Obesity due to congenital leptin deficiency	Conflicting classifications of pathogenicity (Dec 10, 2023)
7-128254433-C-G		LEP-related disorder	Likely benign (Apr 20, 2023)
7-128254434-G-A		Leptin dysfunction • Obesity due to congenital leptin deficiency	Pathogenic (Jan 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LEP	protein_coding	protein_coding	ENST00000308868	2	16345

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.465	0.512	125738	0	9	125747	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.910	62	85.7	0.723	0.00000441	1077
Missense in Polyphen		16	28.518	0.56105		388
Synonymous	-2.41	56	37.3	1.50	0.00000214	343
Loss of Function	1.82	1	5.70	0.175	2.48e-7	64

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.000229	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:17344214, PubMed:15899045, PubMed:19688109). In the hypothalamus, 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. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:8589726, PubMed:11460888, PubMed:19688109, PubMed:24340098, PubMed:25060689). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption (PubMed:24340098). Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:17344214). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (PubMed:18242580). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:11460888). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro- inflammatory mediators. Increases cytotoxic ability of NK cells (PubMed:12504075). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045, PubMed:19688109). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T-cell proliferation and reduces autophagy during TCR (T-cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689). {ECO:0000250|UniProtKB:P41160, ECO:0000250|UniProtKB:P50596, ECO:0000269|PubMed:11460888, ECO:0000269|PubMed:12504075, ECO:0000269|PubMed:15899045, ECO:0000269|PubMed:17344214, ECO:0000269|PubMed:18242580, ECO:0000269|PubMed:19688109, ECO:0000269|PubMed:24340098, ECO:0000269|PubMed:25060689, ECO:0000269|PubMed:8589726, ECO:0000305|PubMed:15122202, ECO:0000305|PubMed:25232147}.
• Disease: DISEASE: Leptin deficiency (LEPD) [MIM:614962]: A rare disease characterized by low levels of serum leptin, severe hyperphagia and intractable obesity from an early age. {ECO:0000269|PubMed:25551525, ECO:0000269|PubMed:9500540}. 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;Transcriptional regulation of white adipocyte differentiation;Adipogenesis;Spinal Cord Injury;Differentiation of white and brown adipocyte;Transcription factor regulation in adipogenesis;Leptin and adiponectin;Leptin Insulin Overlap;Signal Transduction;reversal of insulin resistance by leptin;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Signaling by Leptin;Leptin;GPCR signaling-G alpha i;TSH;HIF-1-alpha transcription factor network;Signaling events mediated by PTP1B (Consensus)

Recessive Scores

• pRec: 0.782

Intolerance Scores

• loftool: 0.373
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.26

Haploinsufficiency Scores

• pHI: 0.370
• hipred: N
• hipred_score: 0.402

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.946

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lep
• Phenotype: growth/size/body region 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); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory 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); hematopoietic system 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); reproductive system phenotype; pigmentation phenotype; neoplasm; digestive/alimentary 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); vision/eye phenotype; immune system phenotype

Zebrafish Information Network

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

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;angiogenesis;ovulation from ovarian follicle;response to hypoxia;placenta development;regulation of endothelial cell proliferation;response to dietary excess;cardiac muscle hypertrophy;glucose metabolic process;regulation of gluconeogenesis;energy reserve metabolic process;glycerol biosynthetic process;lipid metabolic process;fatty acid beta-oxidation;phagocytosis;tyrosine phosphorylation of STAT protein;female pregnancy;circadian rhythm;cholesterol metabolic process;bile acid metabolic process;regulation of blood pressure;determination of adult lifespan;adult feeding behavior;regulation of signaling receptor activity;negative regulation of autophagy;negative regulation of lipid storage;positive regulation of phosphatidylinositol 3-kinase signaling;response to activity;sexual reproduction;central nervous system neuron development;insulin secretion;T cell differentiation;regulation of intestinal cholesterol absorption;positive regulation of TOR signaling;negative regulation of appetite;prostaglandin secretion;response to estradiol;interleukin-12 production;positive regulation of tumor necrosis factor production;regulation of natural killer cell activation;regulation of natural killer cell proliferation;response to insulin;response to vitamin E;leptin-mediated signaling pathway;positive regulation of luteinizing hormone secretion;positive regulation of peroxisome proliferator activated receptor signaling pathway;bone mineralization involved in bone maturation;negative regulation of appetite by leptin-mediated signaling pathway;positive regulation of T cell proliferation;regulation of natural killer cell mediated cytotoxicity;positive regulation of protein import into nucleus;hormone metabolic process;positive regulation of tyrosine phosphorylation of STAT protein;glucose homeostasis;eating behavior;negative regulation of apoptotic process;positive regulation of ion transport;positive regulation of MAPK cascade;cellular response to leptin stimulus;response to ethanol;regulation of angiogenesis;negative regulation of vasoconstriction;negative regulation of glucose import;positive regulation of JAK-STAT cascade;positive regulation of insulin receptor signaling pathway;regulation of bone remodeling;positive regulation of follicle-stimulating hormone secretion;positive regulation of developmental growth;regulation of insulin secretion;regulation of steroid biosynthetic process;intestinal absorption;leukocyte tethering or rolling;regulation of nitric-oxide synthase activity;regulation of cell cycle;positive regulation of protein kinase B signaling;regulation of lipoprotein lipid oxidation;adipose tissue development;negative regulation of cartilage development;negative regulation of glucagon secretion;cellular response to L-ascorbic acid;cellular response to retinoic acid;interleukin-6 secretion;interleukin-8 secretion;regulation of brown fat cell differentiation;bone growth;positive regulation of cold-induced thermogenesis;regulation of cytokine production involved in inflammatory response;positive regulation of p38MAPK cascade;positive regulation of fat cell apoptotic process;activation of protein kinase C activity;positive regulation of reactive oxygen species metabolic process;negative regulation of glutamine transport;positive regulation of hepatic stellate cell activation
• Cellular component: extracellular region;extracellular space;cytoplasm
• Molecular function: hormone activity;peptide hormone receptor binding