Human Gene Module / Chromosome 7 / KMT2C

KMT2CLysine (K)-specific methyltransferase 2C

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
10 / 14
Rare Variants / Common Variants
45 / 0
Aliases
KMT2C, HALR,  MLL3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
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 GeneOMIMUniProtEntrez GeneHumanBasePubMed
Reports related to KMT2C (14 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 Support Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Kleefstra T , et al. (2012) No -
3 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
5 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
6 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
7 Recent Recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Homsy J , et al. (2016) No ASD, DD
8 Support The Contribution of Mosaic Variants to Autism Spectrum Disorder. Freed D and Pevsner J (2016) Yes -
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
10 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
11 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
12 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
13 Recent Recommendation Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. Koemans TS , et al. (2017) No ASD
14 Support Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. Faundes V , et al. (2017) No ASD, microcephaly
Rare Variants   (45)
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)
c.4441C>T p.Arg1481Ter stop_gained Unknown - Simplex 22726846 Kleefstra T , 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 p.Glu1120Ter 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)
C>T p.Trp1056Ter stop_gained De novo - - 28714951 Lim ET , et al. (2017)
c.14416C>G p.Arg4806Gly missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.5216del p.Pro1739LeufsTer2 frameshift_variant De novo - - 29069077 Koemans TS , et al. (2017)
c.7550C>G p.Ser2517Ter stop_gained De novo - - 29069077 Koemans TS , et al. (2017)
c.1690A>T p.Lys564Ter stop_gained De novo - - 29069077 Koemans TS , et al. (2017)
c.10812_10815del p.Lys3605GlufsTer24 frameshift_variant De novo - - 29069077 Koemans TS , et al. (2017)
- - copy_number_loss De novo - - 29069077 Koemans TS , et al. (2017)
c.4744G>T p.Gly1582Ter stop_gained De novo - - 29276005 Faundes V , et al. (2017)
c.8849_8850delAT p.His2950ArgfsTer17 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
c.14526dupG p.Pro4843AlafsTer12 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Score remained at 2.1 + S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2018
2S
icon
2.1 + S

Score remained at 2.1 + S

Description

2S

Reports Added
[Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.2017]
10/1/2017
2
icon
2S

Score remained at 2S

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). Koemans et al., 2017 identified four patients with intellectual disability, language delay, and motor delay that carried de novo LoF variants in the KMT2C gene; two of these patients presented with autism, one patient presented with PDD-NOS, and one presented with autistic traits.

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017] [Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder.2017] [Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability.2012]
7/1/2017
2
icon
2

Score remained at 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
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
2
icon
2

Score remained at 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]
10/1/2016
2
icon
2

Score remained at 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

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The Contribution of Mosaic Variants to Autism Spectrum Disorder.2016]
1/1/2016
2
icon
2

Score remained at 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

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder.2014]
4/1/2015
2
icon
2

Score remained at 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

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
10/1/2014
icon
2

Increased from to 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

Krishnan Probability Score

Score 0.48416136395112

Ranking 7586/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 1

Ranking 16/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.984

Ranking 36/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.00047927143184048

Ranking 17/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 45

Ranking 41/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
CNVs associated with KMT2C(1 CNVs)
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7q36.1 25 Deletion-Duplication 40  /  117
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