GeneBe

KMT2E

protein-coding

lysine methyltransferase 2E (inactive), the group of PHD finger proteins|SET domain containing|Lysine methyltransferases

Gene summary

This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a central SET domain. Overexpression of the protein inhibits cell cycle progression. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

Previous symbols:
  • MLL5

MANE transcript

NM_182931.3

Inheritance

AD

ClinVar variants

P:157U:732B:415

Top phenotype

O'Donnell-Luria-Rodan syndrome

gnomAD constraint

pLI —, LoF o/e 0.01

Max pathogenic AF

—

Genomic locus

chr7:104,940,943-105,115,019

External References & Databases

Ensembl (ENSG00000005483)NCBI Gene (55904)OMIM (608444)HGNC:18541GenCCUniProt (Q8IZD2)AlphaFoldClinVar (KMT2E)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~174.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*KMT2E* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2019 (O’Donnell-Luria et al., PMID: 31079897). Complex neurodevelopmental disorder in relation to variants in *KMT2E* was originally termed as O'Donnell-Luria-Rodan syndrome (ODLURO), a neurodevelopmental disorder characterized by global developmental delay, speech delay, variably delayed intellectual development, and subtle dysmorphic features. Some patients may also have autism, seizures, hypotonia, and/or feeding difficulties. Ten variants, mostly *de novo* (missense, in-frame indel, nonsense, and frameshift), that have been reported in 10 probands in 3 publications (PMIDs: 31079897, 33111303, 35273928) are included in this curation. Of note, individuals with protein truncating variants tended to present with milder neurodevelopmental phenotypes in contrast to individuals with missense variants presented, who presented with epilepsy, including infantile-onset epileptic encephalopathy, and more severe developmental delays. (O’Donnell-Luria et al., PMID: 31079897). More evidence is available in the literature, including chromosome 7q22.2-22.3 microdeletions involving KMT2E, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be LOF. At the time of this curation, there is no experimental evidence to support this gene-disease relationship. In summary, *KMT2E* is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date August 2, 2022 (SOP Version 9).

O'Donnell-Luria-Rodan syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032793

Submitter: Ambry Genetics

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

O'Donnell-Luria-Rodan syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032793

Submitter: Illumina

O'Donnell-Luria-Rodan syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032793

Submitter: G2P

O'Donnell-Luria-Rodan syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032793

Submitter: Labcorp Genetics (formerly Invitae)

O'Donnell-Luria-Rodan syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032793

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

O'Donnell-Luria-Rodan syndromeAD

Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 31079897Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KMT2E variants in ClinVar

19 Conditions Cataloged
not providedTotal: 1107
Inborn genetic diseasesTotal: 276
O'Donnell-Luria-Rodan syndromeTotal: 161
not specifiedTotal: 142
KMT2E-related disorderTotal: 102
See casesTotal: 35
Neurodevelopmental disorderTotal: 4
Neurodevelopmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182931.3. 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
2
clinvar
7
clinvar
243
clinvar
7
clinvar
 259
missense
1
clinvar
9
clinvar
696
clinvar
119
clinvar
43
clinvar
 868
nonsense
18
clinvar
19
clinvar
2
clinvar
1
clinvar
 40
start loss
0
frameshift
55
clinvar
36
clinvar
20
clinvar
1
clinvar
1
clinvar
 113
splice donor/acceptor (+/-2bp)
3
clinvar
14
clinvar
7
clinvar
 24
Total7780732364511304

Highest pathogenic variant AF is 0.000014365044

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_182931.3RefSeqNP_891847.125MANE Select
ENST00000311117.8EnsemblENSP00000312379.325MANE Select
NM_001410908.1RefSeqNP_001397837.124Standard
NM_018682.4RefSeqNP_061152.325Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysine degradation - Homo sapiens (human)
  • Histone Modifications
  • Gene expression (Transcription)
  • Generic Transcription Pathway
  • PKMTs methylate histone lysines

Biological Process

  • neutrophil mediated immunity
  • DNA methylation
  • cell cycle arrest
  • erythrocyte differentiation
  • histone lysine methylation

Molecular Function

  • protein binding
  • histone-lysine N-methyltransferase activity
  • enzyme binding
  • methylated histone binding
  • metal ion binding

Cellular Component

  • chromatin
  • nucleus
  • nucleoplasm
  • cytoplasm
  • microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000311117
Coding exons
25
Length
100183
Individuals with no LoFs
125706
Homozygous LoFs
0
Heterozygous LoFs
39
Defined
125745
p
0.000155
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.428499740.8720.000050012103
Missense (PolyPhen)3947.4690.82158441
Synonymous-2.604103481.180.00001863673
Loss of Function8.11178.60.01270.000003761044

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000210.00018rare
Latino/Admixed American0.000170.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000280.00027rare
Finnish0.0000960.000092rare
European (Non-Finnish)0.000160.00015rare
South Asian0.000300.00029rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (PubMed:23629655, PubMed:24130829, PubMed:23798402). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (PubMed:24130829, PubMed:23798402). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (By similarity). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:14718661, PubMed:18573682, PubMed:19264965, PubMed:23629655). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (By similarity). {ECO:0000250|UniProtKB:Q3UG20, ECO:0000269|PubMed:14718661, ECO:0000269|PubMed:18573682, ECO:0000269|PubMed:23629655, ECO:0000269|PubMed:23798402, ECO:0000269|PubMed:24130829}.;

Recessive Scores

pRec
0.114

Intolerance Scores

RVIS EVS
-1.45
RVIS percentile EVS
3.9

Essentials

Essential (CRISPR)
N
Essential (gene trap)
N

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.