EZH2

enhancer of zeste 2 polycomb repressive complex 2 subunit, the group of Polycomb repressive complex 2|Lysine methyltransferases|Myb/SANT domain containing|SET domain containing

Basic information

Region (hg38): 7:148807257-148884321

Links

ENSG00000106462 ∙ NCBI:2146 ∙ OMIM:601573 ∙ HGNC:3527 ∙ Uniprot:Q15910 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Weaver syndrome (Strong), mode of inheritance: AD
• Weaver syndrome (Definitive), mode of inheritance: AD
• Weaver syndrome (Supportive), mode of inheritance: AD
• Weaver syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Weaver syndrome	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic	4366187; 22177091

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EZH2 gene.

• Weaver syndrome (6 variants)
• EZH2-related disorder (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EZH2 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			1	104	7	112
missense	6	22	133	15	8	184
nonsense		1	5			6
start loss			1			1
frameshift		2	7			9
inframe indel		2	9			11
splice donor/acceptor (+/-2bp)			3			3
splice region			13	32	7	52
non coding			6	115	35	156
Total	6	27	165	234	50

Variants in EZH2

This is a list of pathogenic ClinVar variants found in the EZH2 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-148807371-T-C		Weaver syndrome	Likely benign (Jun 14, 2016)
7-148807624-AG-A		not specified • Weaver syndrome	Benign (Aug 10, 2021)
7-148807652-G-C		Weaver syndrome	Uncertain significance (Jul 25, 2021)
7-148807666-T-C		Weaver syndrome	Likely pathogenic (May 16, 2013)
7-148807667-T-A		Weaver syndrome	Pathogenic (Jul 26, 2019)
7-148807668-T-C		Weaver syndrome	Uncertain significance (Jan 04, 2019)
7-148807669-C-A			Uncertain significance (May 02, 2023)
7-148807669-C-T		Weaver syndrome • EZH2-related disorder	Pathogenic (Nov 12, 2023)
7-148807670-G-A		not specified • Weaver syndrome	Likely benign (Aug 01, 2023)
7-148807669-C-CGAT		Weaver syndrome	Uncertain significance (Apr 04, 2024)
7-148807676-G-A		Weaver syndrome • EZH2-related disorder	Likely benign (Dec 19, 2023)
7-148807679-A-G		Weaver syndrome	Likely benign (Mar 31, 2023)
7-148807681-A-G			Likely pathogenic (Jul 20, 2016)
7-148807682-C-G		Weaver syndrome	Uncertain significance (Apr 15, 2023)
7-148807681-A-ACTT		Weaver syndrome	Likely pathogenic (Aug 09, 2018)
7-148807685-C-A		Weaver syndrome	Likely benign (Dec 08, 2018)
7-148807688-G-A		Weaver syndrome	Likely benign (Dec 09, 2022)
7-148807689-G-T		Weaver syndrome	Likely pathogenic (Jul 18, 2017)
7-148807690-C-T			Uncertain significance (Dec 20, 2023)
7-148807690-C-CATCAGCCT		Weaver syndrome	Pathogenic (Aug 11, 2022)
7-148807699-G-A		not specified	Uncertain significance (Jan 07, 2016)
7-148807703-G-A		Weaver syndrome	Likely benign (Oct 13, 2023)
7-148807703-G-C		Weaver syndrome	Pathogenic (Aug 11, 2022)
7-148807704-T-TATCTGAAACAAC		Weaver syndrome	Likely pathogenic (Aug 24, 2018)
7-148807708-T-C		Weaver syndrome	Uncertain significance (Aug 03, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EZH2	protein_coding	protein_coding	ENST00000320356	19	76939

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000466	109672	0	2	109674	0.00000912

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.68	154	426	0.362	0.0000236	5005
Missense in Polyphen		29	145.5	0.19932		1811
Synonymous	-1.18	163	145	1.12	0.00000796	1335
Loss of Function	5.81	2	43.2	0.0463	0.00000226	524

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000813	0.0000813
Ashkenazi Jewish	0.00	0.00
East Asian	0.000124	0.0000616
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.000124	0.0000616
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys- 27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2 (PubMed:22323599). Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non- histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription. {ECO:0000269|PubMed:14532106, ECO:0000269|PubMed:15225548, ECO:0000269|PubMed:15231737, ECO:0000269|PubMed:15385962, ECO:0000269|PubMed:16179254, ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:16618801, ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16936726, ECO:0000269|PubMed:17210787, ECO:0000269|PubMed:17344414, ECO:0000269|PubMed:18285464, ECO:0000269|PubMed:19026781, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:22323599, ECO:0000269|PubMed:23063525, ECO:0000269|PubMed:24474760}.
• Disease: DISEASE: Weaver syndrome (WVS) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. {ECO:0000269|PubMed:22177091, ECO:0000269|PubMed:22190405, ECO:0000269|PubMed:23239504, ECO:0000269|PubMed:26694085, ECO:0000269|PubMed:28229514}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lysine degradation - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;miRs in Muscle Cell Differentiation;Cell Differentiation - Index expanded;Histone Modifications;Endoderm Differentiation;Interactome of polycomb repressive complex 2 (PRC2);Oxidative Stress Induced Senescence;MECP2 and Associated Rett Syndrome;Tumor suppressor activity of SMARCB1;EMT transition in Colorectal Cancer;Signal Transduction;Epigenetic regulation of gene expression;Gene expression (Transcription);the prc2 complex sets long-term gene silencing through modification of histone tails;Transcriptional Regulation by E2F6;Generic Transcription Pathway;Oxidative Stress Induced Senescence;Cellular Senescence;Cellular responses to stress;PKMTs methylate histone lysines;RNA Polymerase II Transcription;Chromatin modifying enzymes;Cellular responses to external stimuli;Regulation of PTEN gene transcription;PTEN Regulation;PIP3 activates AKT signaling;Chromatin organization;Intracellular signaling by second messengers;PRC2 methylates histones and DNA (Consensus)

Recessive Scores

• pRec: 0.315

Intolerance Scores

• loftool: 0.0135
• rvis_EVS: -0.54
• rvis_percentile_EVS: 20.54

Haploinsufficiency Scores

• pHI: 0.975
• hipred: Y
• hipred_score: 0.825
• ghis: 0.701

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.966

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ezh2
• 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); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; 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); 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); normal phenotype; neoplasm; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton 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)

Zebrafish Information Network

• Gene name: ezh2
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: detached from

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;DNA methylation;chromatin organization;regulation of transcription, DNA-templated;positive regulation of cell population proliferation;positive regulation of epithelial to mesenchymal transition;regulation of gliogenesis;skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration;cardiac muscle hypertrophy in response to stress;histone methylation;cerebellar cortex development;hippocampus development;response to estradiol;negative regulation of transcription elongation from RNA polymerase II promoter;cellular response to trichostatin A;hepatocyte homeostasis;regulation of circadian rhythm;positive regulation of MAP kinase activity;negative regulation of DNA-binding transcription factor activity;positive regulation of GTPase activity;negative regulation of epidermal cell differentiation;negative regulation of gene expression, epigenetic;negative regulation of transcription, DNA-templated;negative regulation of retinoic acid receptor signaling pathway;rhythmic process;negative regulation of striated muscle cell differentiation;cellular response to hydrogen peroxide;G1 to G0 transition;negative regulation of G0 to G1 transition;histone H3-K27 methylation;protein localization to chromatin;positive regulation of protein serine/threonine kinase activity;liver regeneration;histone H3-K27 trimethylation;positive regulation of dendrite development;positive regulation of cell cycle G1/S phase transition;response to tetrachloromethane;negative regulation of G1/S transition of mitotic cell cycle
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;cytoplasm;ESC/E(Z) complex;pronucleus
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II core promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;chromatin binding;protein binding;protein-lysine N-methyltransferase activity;histone-lysine N-methyltransferase activity;chromatin DNA binding;histone methyltransferase activity;ribonucleoprotein complex binding;histone methyltransferase activity (H3-K27 specific);primary miRNA binding;promoter-specific chromatin binding