GeneBe

EZH2

protein-coding

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

Gene summary

This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_004456.5

Inheritance

AD

ClinVar variants

P:45U:253B:177

Top phenotype

Weaver syndrome

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr7:148,807,257-148,884,321

External References & Databases

Ensembl (ENSG00000106462)NCBI Gene (2146)OMIM (601573)HGNC:3527GenCCUniProt (Q15910)AlphaFoldClinVar (EZH2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~77.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Weaver syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010193

Submitter: ClinGen

*EZH2* was first reported in relation to autosomal dominant Weaver syndrome in 2011 (PMID: 22190405). Weaver syndrome (WS) is a rare multisystem disorder characterized by tall stature, a typical facial appearance, and variable intellectual disability. Additional features may include camptodactyly, advanced bone age, soft doughy skin, umbilical hernia, and a low hoarse cry (PMIDs: 22190405, 23865096, 24214728). *EZH2* variants have also been observed in individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome (PMIDs: 22190405, 24214728). *EZH2* variants, primarily missense, as well as a small number of nonsense, frameshift, and in-frame insertion or deletion variants, have been identified in over 50 individuals with Weaver syndrome or overgrowth (PMIDs: 22177091, 22190405, 24214728, 32243864). Truncating variants are uncommon and to date have only been identified in the last or penultimate exon (PMID: 24214728, ClinVar variation ID: 207471). Only 11 probands are included in this curation because the maximum score for genetic evidence has been reached. *EZH2* encodes a histone methyltransferase. Pathogenic variants in EZH2 generate a highly specific DNA methylation signature (PMID: 32243864). The disease mechanism is loss of function (PMIDs: 26694085, 29244146, 32243864). However, the fact that truncating variants have only been reported in the last or penultimate exon and may therefore escape nonsense-mediated decay suggests that they may not act through haploinsufficiency (PMID: 22190405, 24214728). This gene-disease relationship is also supported by experimental evidence, including protein interaction, functional alterations, and mouse model studies (PMIDs: 15225548, 26694085, 29244146, 32243864). In summary, there is definitive evidence supporting the relationship between *EZH2* and Weaver syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 3, 2022 (SOP Version 9).

Weaver syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010193

Submitter: Orphanet

Weaver syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010193

Submitter: G2P

Weaver syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010193

Submitter: PanelApp Australia

Weaver syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010193

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Weaver syndromeAD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 4366187; 22177091Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EZH2 variants in ClinVar

10 Conditions Cataloged
Weaver syndromeTotal: 524
not providedTotal: 192
not specifiedTotal: 85
Inborn genetic diseasesTotal: 34
EZH2-related disorderTotal: 32
Neurodevelopmental disorderTotal: 1
Hereditary cancer-predisposing syndromeTotal: 1
Fetal anomalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004456.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
141
clinvar
2
clinvar
 150
missense
6
clinvar
33
clinvar
216
clinvar
29
clinvar
5
clinvar
 289
nonsense
1
clinvar
2
clinvar
8
clinvar
 11
start loss
1
clinvar
 1
frameshift
1
clinvar
2
clinvar
14
clinvar
 17
splice donor/acceptor (+/-2bp)
7
clinvar
 7
Total8372531707475

Highest pathogenic variant AF is 0.0000065717704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 113 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004456.5RefSeqNP_004447.219MANE Select
ENST00000320356.7EnsemblENSP00000320147.219MANE Select
NM_001203247.2RefSeqNP_001190176.119Standard
NM_001203248.2RefSeqNP_001190177.119Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ezh2Danio rerio

Structure: cardiac muscle cell

Quality: detached from

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

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

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

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm
  • cytoplasm
  • ESC/E(Z) complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000320356
Coding exons
19
Length
76939
Individuals with no LoFs
109672
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
109674
p
0.00000912
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.681544260.3620.00002365005
Missense (PolyPhen)29145.50.199321811
Synonymous-1.181631451.120.000007961335
Loss of Function5.81243.20.04630.00000226524

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000810.000040rare
Ashkenazi Jewish00.0absent
East Asian0.000120.000062rare
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.315

Intolerance Scores

LoFtool
0.0135
RVIS EVS
-0.54
RVIS percentile EVS
20.54

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.966

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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