KMT2E

Chr 7AD

lysine methyltransferase 2E (inactive)

Also known as: HDCMC04P, MLL5, NKp44L, ODLURO, SETD5B

NCBI Gene: 55904 ENSG00000005483 OMIM: 608444

This gene encodes a chromatin-modifying enzyme that regulates gene transcription by binding to tri-methylated histone H3 and plays key roles in cell cycle progression and hematopoietic differentiation. Mutations cause O'Donnell-Luria-Rodan syndrome, a neurodevelopmental disorder with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its critical biological importance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— KMT2E

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

139 unique Pathogenic / Likely Pathogenic· 697 VUS of 1390 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KMT2E

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 8.11

OE 0.01 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.42Z-score

OE missense 0.87 (0.82–0.92)

849 obs / 973.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.01 (0.00–0.06)

0≤0.351.4

Missense OE?0.87 (0.82–0.92)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 78.6Missense obs/exp: 849 / 973.7Syn Z: -2.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKMT2E-related neurodevelopmental disorder/O'Donnell-Luria-Rodan syndromeLOFAD

This gene — mechanism propensity

0.16100th %ile

GOF

0.1899th %ile

LOF

0.92top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 89% of P/LP variants are LoF · LOEUF 0.06 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31079897 ↗

ClinVar Variant Classifications

1390 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic70

Likely Pathogenic69

VUS697

Likely Benign388

Benign86

Conflicting54

Pathogenic

Likely Pathogenic

697

VUS

388

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	69	1	0	0	70
Likely Pathogenic	55	9	3	2	69
VUS	21	644	28	4	697
Likely Benign	0	67	106	215	388
Benign	1	48	22	15	86
Conflicting	—				54
Total	146	769	159	236	1,364

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

27 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap KMT2E — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →