KMT2C

Chr 7AD

lysine methyltransferase 2C

Also known as: HALR, KLEFS2, MLL3

NCBI Gene: 58508 ENSG00000055609 UniProt: Q8NEZ4 OMIM: 606833

This histone methyltransferase catalyzes H3K4 methylation and functions in chromatin remodeling and transcriptional regulation. Mutations cause Kleefstra syndrome 2, a neurodevelopmental disorder with intellectual disability, developmental delay, and dysmorphic features, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 1), consistent with its essential role in normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— KMT2C

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · 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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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 12.59

OE 0.08 (0.06–0.12)

Highly constrained

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

Missense Constraint?

2.14Z-score

OE missense 0.88 (0.85–0.91)

2226 obs / 2528.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.06–0.12)

0≤0.351.4

Missense OE?0.88 (0.85–0.91)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 18 / 219.2Missense obs/exp: 2226 / 2528.2Syn Z: -0.53

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKMT2C-related intellectual disabilityLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.06100th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.12 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFGirirajan et al. (2013) conducted a large-scale case-control study (2588 patients; 580 controls) of an autism patient cohort to identify segmental duplication mediated and associated recurrent genomic hotspots for copy number variants, and dosage sensitive genes, using custom targeted high density a1

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

References