Human Gene Module / Chromosome 7 / KMT2C

KMT2CLysine (K)-specific methyltransferase 2C 

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 9
Rare Variants / Common Variants
34 / 0
Aliases
KMT2C, HALR,  MLL3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
7q36.1
Associated Disorders
DD/NDD, ASD
Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

Histone methyltransferase that 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.

External Links
Gene CardEntrez GeneOMIMUniProt
Reports related to KMT2C (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
5 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
6 Recent recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Homsy J , et al. (2016) No ASD, DD
7 Support The Contribution of Mosaic Variants to Autism Spectrum Disorder. Freed D and Pevsner J (2016) Yes -
8 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.14073C>A p.Tyr4691Ter stop_gained De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
del(C) - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.13761G>C p.Trp4587Cys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3373C>T p.Pro1125Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6275A>T p.Asp2092Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1252C>T p.Leu418Phe missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11662T>G p.Leu3888Val missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6136C>G p.Pro2046Ala missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5006C>G p.Pro1669Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6720A>C p.Arg2240Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.14621G>A p.Arg1487Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.404G>A p.Ser135Asn missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11486G>A p.Gly3829Asp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8342T>A p.Ile2781Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.10102G>A p.Gly3368Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9530G>A p.Arg3177His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7787G>A p.Arg2596Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6985G>A p.Gly2329Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5006C>G p.Pro1669Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3782T>G p.Val1261Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9065C>T p.Thr3022Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8076T>A p.Asp2692Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6386A>G p.Arg2129Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6197G>A p.Arg2066Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6164A>T p.Asp2055Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5180C>T p.Pro1727Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5171G>T p.Ser1724Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4775C>T p.Ser1592Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2861C>T p.Thr954Ile missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.13298C>T p.Ala4433Val missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
C>A - stop_gained De novo - - 26785492 Homsy J , et al. (2016)
c.6592_6593del p.Arg2198AlafsTer3 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1378delT p.Tyr460fs frameshift_variant De novo - Multiplex 28263302 C Yuen RK , et al. (2017)
insT p.? splice_site_variant Familial - Simplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in the KMT2C gene was identified in an ASD proband from the Simon Simplex Collection (PMIDs 22495309), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KMT2C as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). Additional de novo probably damaging missense variants in KMT2C were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015). A de novo LoF variant in KMT2C was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015).

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

04-01-2017
2

Initial score established: 2

Description

A de novo LoF variant in the KMT2C gene was identified in an ASD proband from the Simon Simplex Collection (PMIDs 22495309), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KMT2C as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). Additional de novo probably damaging missense variants in KMT2C were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015). A de novo LoF variant in KMT2C was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The Contribution of Mosaic Variants to Autism Spectrum Disorder.2016]
CNVs associated with KMT2C(1 CNVs)
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7q36.1 21 Deletion-Duplication 35  /  109
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