KMT2C

protein-coding

lysine methyltransferase 2C, 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 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]

Previous symbols:

MLL3

MANE transcript

NM_170606.3

Inheritance

ClinVar variants

P:195U:1350B:994

Top phenotype

Kleefstra syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr7:152,134,922-152,436,644

External References & Databases

Ensembl (ENSG00000055609)

Transcript & Mutation Effects

hg38 • Region Span ~301.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kleefstra syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054701

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

*KMT2C* encodes a lysine methyltransferase that is part of the COMPASS complex (complex of proteins associated with SET1) involved in chromatin regulation. The relationship between *KMT2C* and syndromic intellectual disability (ID) was first reported in 2012 (Kleefstra et al., PMID: 22726846) in one individual from a cohort of patients with features of Kleefstra syndrome, which is characterized by ID, childhood hypotonia, and distinctive facial features. The affected individual harboured a heterozygous nonsense variant of unknown inheritance. Since then, at least eight *de novo* variants (3 nonsense, 4 frameshift and 1 deletion encompassing the entire gene) have been reported with detailed phenotypic descriptions (PMIDs: 29069077, 29276005). Affected individuals presented with a range of ID, language and motor delay, and mild dysmorphic features, some of which resemble Kleefstra-like facial dysmorphisms; additional features include microcephaly in 6 individuals and childhood hypotonia in 4 individuals. Autism spectrum disorder (ASD) or autistic traits were noted in three males and one female (PMIDs: 29069077, 29276005). Numerous truncating, mostly de novo variants in *KMT2C* have also been reported in large cohort studies of ASD or ID (PMIDs: 21658581, 27824329, 28263302, 31981491, 33057194). The disease mechanism is haploinsufficiency. The gene-disease relationship is supported by experimental evidence of *KMT2C* interactions with proteins in the COMPASS complex implicated in ID (e.g., *KMT2D, KDM6A*), and by a knockout model of the *KMT2C* fly ortholog *trr* showing deficits in short term memory and learning (PMID: 28605393). In summary, there is definitive evidence to support the relationship between *KMT2C* and autosomal dominant syndromic intellectual disability. This was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 2, 2022 (SOP Version 8).

Kleefstra syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054701

Submitter: Ambry Genetics

Kleefstra syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054701

Submitter: Broad Center for Mendelian Genomics

Kleefstra syndrome 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0054701

Submitter: Illumina

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Kleefstra syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054701

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Kleefstra syndrome 2AD

Manifestation: 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: 22726846; 29069077

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KMT2C variants in ClinVar

27 Conditions Cataloged

not providedTotal: 1765

Inborn genetic diseasesTotal: 550

not specifiedTotal: 420

Kleefstra syndrome 2Total: 334

KMT2C-related disorderTotal: 182

KMT2C-related NDDTotal: 73

Intellectual disabilityTotal: 13

See casesTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_170606.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	13 clinvar	362 clinvar	72 clinvar	448
missense		23 clinvar	1259 clinvar	484 clinvar	71 clinvar	1837
nonsense	36 clinvar	29 clinvar	30 clinvar	1 clinvar	1 clinvar	97
start loss						0
frameshift	57 clinvar	33 clinvar	13 clinvar			103
splice donor/acceptor (+/-2bp)	5 clinvar	11 clinvar	35 clinvar	2 clinvar	1 clinvar	54
Total	98	97	1350	849	145	2539

Highest pathogenic variant AF is 0.000034695975

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_170606.3	RefSeq	NP_733751.2	59	MANE Select
ENST00000262189.11	Ensembl	ENSP00000262189.6	59	MANE Select
ENST00000360104.8	Ensembl	ENSP00000353218.4	31	Standard
ENST00000418061.2	Ensembl	ENSP00000408001.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Pathways Affected in Adenoid Cystic Carcinoma
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

regulation of megakaryocyte differentiation
positive regulation of transcription by RNA polymerase II
histone H3-K4 methylation

Molecular Function

DNA binding
transcription coactivator activity
RNA binding
protein binding
transferase activity, transferring acyl groups

Cellular Component

nucleus
nucleoplasm
histone methyltransferase complex
MLL3/4 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262189
Coding exons: 59
Length: 301081
Individuals with no LoFs: 124784
Homozygous LoFs: 0
Heterozygous LoFs: 964
Defined: 125748
p: 0.00384

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	2226	2.53e+3	0.880	0.000133	31901
Missense (PolyPhen)		680	1069.8	0.63562		13392
Synonymous	-0.530	919	899	1.02	0.0000474	9586
Loss of Function	12.6	18	219	0.0821	0.0000122	2645

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0067	0.0054	notable
Latino/Admixed American	0.0035	0.0031	notable
Ashkenazi Jewish	0.0024	0.0022	notable
East Asian	0.0027	0.0023	notable
Finnish	0.0025	0.0022	notable
European (Non-Finnish)	0.0038	0.0033	notable
South Asian	0.010	0.0084	notable
Other	0.0046	0.0041	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase. Methylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Central component of the MLL2/3 complex, a coactivator complex of nuclear receptors, involved in transcriptional coactivation. KMT2C/MLL3 may be a catalytic subunit of this complex. May be involved in leukemogenesis and developmental disorder. {ECO:0000269|PubMed:17500065}.;
Disease: DISEASE: Kleefstra syndrome 2 (KLEFS2) [MIM:617768]: A form of Kleefstra syndrome, an autosomal dominant disease characterized by variable mental retardation, psychomotor developmental delay, seizures, behavioral abnormalities, and facial dysmorphisms. {ECO:0000269|PubMed:22726846, ECO:0000269|PubMed:29069077}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: -2.52
RVIS percentile EVS: 0.91

Essentials

Essential (CRISPR): N
Essential (gene trap): H

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High