Human Gene Module / Chromosome 7 / KMT2C

KMT2CLysine (K)-specific methyltransferase 2C

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
29 / 44
Rare Variants / Common Variants
163 / 0
Aliases
KMT2C, HALR,  MLL3
Associated Syndromes
Kleefstra syndrome, Kleefstra syndrome 2, ASD, DD, ID, Kleefstra syndrome 2, DD, ID, ASD, Kleefstra syndrome 2
Chromosome Band
7q36.1
Associated Disorders
DD/NDD, ASD
Relevance to Autism

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. Three de novo variants (two protein-truncating variants, one missense variant) were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified KMT2C as a candidate gene with a false discovery rate (FDR) 0.01. Additional de novo loss-of-function variants and potentially damaging missense variants in the KMT2C gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KMT2C as a gene reaching exome-wide significance (P < 2.5E-06).

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 CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KMT2C (44 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
15 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
16 Support Mutations in ASH1L confer susceptibility to Tourette syndrome Liu S , et al. (2019) No -
17 Recent recommendation Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype Frega M , et al. (2020) No -
18 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
19 Support Utility of clinical exome sequencing in a complex Emirati pediatric cohort Mahfouz NA et al. (2020) No -
20 Support - Alonso-Gonzalez A et al. (2021) Yes -
21 Support - Brunet T et al. (2021) No -
22 Support - Dhaliwal J et al. (2021) Yes -
23 Support - Tuncay IO et al. (2022) Yes -
24 Support - Brea-Fernández AJ et al. (2022) Yes -
25 Support - Siano MA et al. (2022) Yes -
26 Support - Chuan Z et al. (2022) No ID
27 Support - Krgovic D et al. (2022) No Autistic behavior
28 Support - Zhou X et al. (2022) Yes -
29 Support - More RP et al. (2023) Yes -
30 Support - Yamada M et al. (2023) Yes -
31 Support - Hu C et al. (2023) Yes -
32 Support - Cirnigliaro M et al. (2023) Yes -
33 Support - Brauer B et al. (2023) Yes -
34 Support - Sheth F et al. (2023) Yes DD, ID
35 Support - Vijay Gupta et al. (2023) Yes DD, ID
36 Support - Qi Yang et al. (2024) No ASD, ADHD
37 Recent Recommendation - Takumi Nakamura et al. () Yes -
38 Support - Kirsten Furley et al. () No ASD, ID
39 Recent recommendation - Dmitrijs Rots et al. (2024) No ASD or autistic features, ADHD or features of ADHD
40 Support - Mathew Wallis et al. (2024) No -
41 Support - Soo-Whee Kim et al. (2024) Yes -
42 Support - Hosneara Akter et al. () No Autistic behavior
43 Support - Ashlesha Gogate et al. (2024) Yes -
44 Support - Steven Laurie et al. (2025) Yes -
Rare Variants   (163)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 29069077 Koemans TS , et al. (2017)
- - translocation De novo - Simplex 36946065 Yamada M et al. (2023)
- - copy_number_loss Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.2770-4dup - splice_region_variant De novo - - 37007974 Hu C et al. (2023)
c.1736-2A>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.9375-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
- - copy_number_loss De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.5344C>T p.Gln1782Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2710C>T p.Arg904Ter stop_gained De novo - - 35571021 Chuan Z et al. (2022)
c.2961C>G p.Tyr987Ter stop_gained Unknown - - 35571021 Chuan Z et al. (2022)
- - copy_number_loss Familial Paternal - 39013459 Dmitrijs Rots et al. (2024)
- - copy_number_loss Familial Paternal - 39095811 Mathew Wallis et al. (2024)
c.3358G>T p.Glu1120Ter stop_gained De novo - - 26785492 Homsy J , et al. (2016)
c.584A>G p.Gln195Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown Not maternal - 39013459 Dmitrijs Rots et al. (2024)
c.4744G>T p.Gly1582Ter stop_gained De novo - - 29276005 Faundes V , et al. (2017)
c.5419C>T p.Gln1807Ter stop_gained Unknown - - 38536866 Kirsten Furley et al. ()
c.1690A>T p.Lys564Ter stop_gained De novo - - 29069077 Koemans TS , et al. (2017)
c.3805G>A p.Gly1269Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4168G>A p.Gly1390Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3315A>G p.Gln1105= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.7550C>G p.Ser2517Ter stop_gained De novo - - 29069077 Koemans TS , et al. (2017)
c.1012+1G>C - splice_site_variant Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.13199G>A p.Arg4400Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.14330G>A p.Arg4777Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.14596C>T p.His4866Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1814-2A>C - splice_site_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.5716C>T p.Arg1906Ter stop_gained De novo - Simplex 31673123 Liu S , et al. (2019)
c.11983C>T p.Arg3995Ter stop_gained De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.6196C>T p.Arg2066Ter stop_gained De novo - - 39013459 Dmitrijs Rots et al. (2024)
c.7828C>T p.Arg2610Ter stop_gained Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.3168G>A p.Trp1056Ter stop_gained De novo - Simplex 28714951 Lim ET , et al. (2017)
c.9166C>T p.Gln3056Ter stop_gained De novo - Simplex 38356881 Qi Yang et al. (2024)
- - copy_number_loss Familial Maternal Multiplex 39013459 Dmitrijs Rots et al. (2024)
c.9375-38C>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.10777T>C p.Tyr3593His missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.1474G>T p.Val492Phe missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.9391C>T p.Gln3131Ter stop_gained Unknown - Simplex 32382396 Mahfouz NA et al. (2020)
c.1017G>C p.Lys339Asn missense_variant De novo - Simplex 35571021 Chuan Z et al. (2022)
c.14073C>A p.Tyr4691Ter stop_gained De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.13394G>A p.Cys4465Tyr missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.307C>T p.Gln103Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.1013-1G>A - splice_site_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.3499+1G>T - splice_site_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.12092C>G p.Pro4031Arg missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.8009C>T p.Thr2670Ile missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.4441C>T p.Arg1481Ter stop_gained Unknown - Simplex 22726846 Kleefstra T , et al. (2012)
c.13229A>G p.Asp4410Gly missense_variant Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.14335C>G p.Arg4779Gly missense_variant Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.1864G>T p.Glu622Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.14031+5G>A - splice_site_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.14344-1G>A - splice_site_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.9244C>T p.Pro3082Ser missense_variant De novo - Simplex 35324822 Siano MA et al. (2022)
c.3393dup p.Asp1132Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.3462del p.Val1156Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.4441C>T p.Arg1481Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.9472C>T p.Gln3158Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.2675G>A p.Gly892Glu missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.13298C>T p.Ala4433Val missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2861C>T p.Thr954Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.11506C>T p.Gln3836Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.11983C>T p.Arg3995Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.13618C>T p.Gln4540Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.13621C>T p.Arg4541Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.14073C>A p.Tyr4691Ter stop_gained De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.14416C>G p.Arg4806Gly missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.2573G>T p.Trp858Leu missense_variant De novo - Simplex 38025430 Vijay Gupta et al. (2023)
c.6415C>T p.Arg2139Ter stop_gained Familial Paternal - 39013459 Dmitrijs Rots et al. (2024)
c.7042C>T p.Gln2348Ter stop_gained Familial Paternal - 39013459 Dmitrijs Rots et al. (2024)
c.8395C>T p.Gln2799Ter stop_gained Familial Maternal - 39013459 Dmitrijs Rots et al. (2024)
c.9451C>T p.Gln3151Ter stop_gained De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.14458C>T p.Gln4820Ter stop_gained Familial Maternal - 39013459 Dmitrijs Rots et al. (2024)
c.14077C>T p.Arg4693Ter stop_gained Unknown - Multiplex 39013459 Dmitrijs Rots et al. (2024)
c.2689C>T p.Arg897Ter stop_gained De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.5216del p.Pro1739LeufsTer2 frameshift_variant De novo - - 29069077 Koemans TS , et al. (2017)
c.3782T>G p.Val1261Gly 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.5006C>G p.Pro1669Arg 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.5180C>T p.Pro1727Leu 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.6197G>A p.Arg2066Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6386A>G p.Asp2129Gly 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.7787G>A p.Arg2596Gln 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.9065C>T p.Thr3022Ile 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.2510C>G p.Pro837Arg missense_variant Unknown - Simplex 39825153 Steven Laurie et al. (2025)
c.14526dup p.Pro4843AlafsTer12 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
c.13761G>C p.Trp4587Cys missense_variant De novo - 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.3233G>A p.Cys1078Tyr missense_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.9891del p.Thr3298ProfsTer2 frameshift_variant De novo - - 39013459 Dmitrijs Rots et al. (2024)
c.13783C>T p.Arg4595Cys missense_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8390dup p.Glu2798GlyfsTer11 frameshift_variant De novo - - 39013459 Dmitrijs Rots et al. (2024)
c.13289T>G p.Leu4430Trp missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.991A>G p.Ile331Val missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.3902C>T p.Ser1301Phe missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.9291G>A p.Met3097Ile missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.5068dup p.Arg1690LysfsTer11 frameshift_variant De novo - Simplex 38356881 Qi Yang et al. (2024)
c.1185-20_1185-7del - splice_region_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.2375C>T p.Pro792Leu missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.13273G>A p.Asp4425Asn missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.8849_8850del p.His2950ArgfsTer17 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
c.11586_11587del p.Pro3863SerfsTer18 frameshift_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.4154A>G p.Asn1385Ser missense_variant Familial Maternal Simplex 35190550 Tuncay IO et al. (2022)
c.4817C>T p.Pro1606Leu missense_variant Familial Paternal Simplex 35190550 Tuncay IO et al. (2022)
c.11851T>C p.Phe3951Leu missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.7443dup p.Phe2482IlefsTer7 splice_site_variant Familial - Simplex 28263302 C Yuen RK et al. (2017)
c.1378del p.Tyr460ThrfsTer35 frameshift_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.404G>A p.Ser135Asn missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1238_1254del p.Tyr413SerfsTer28 frameshift_variant Unknown - - 39013459 Dmitrijs Rots et al. (2024)
c.454del p.Gln152AsnfsTer4 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.11760_11762delinsGG p.Phe3920LeufsTer14 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1951_1952del p.Glu651LysfsTer3 frameshift_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.10812_10815del p.Lys3605GlufsTer24 frameshift_variant De novo - - 29069077 Koemans TS , et al. (2017)
c.1252C>T p.Leu418Phe missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2694del p.Ala899GlnfsTer14 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.9232_9247del p.Gln3078SerfsTer14 frameshift_variant De novo - Simplex 38356881 Qi Yang et al. (2024)
c.3373C>T p.Pro1125Ser 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.6136C>G p.Pro2046Ala 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.6720A>C p.Arg2240Ser missense_variant Familial Paternal 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.1332del p.Ser445LeufsTer10 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.6939dup p.Gly2314TrpfsTer8 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8470dup p.Thr2824AsnfsTer9 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.9621dup p.Ser3208IlefsTer2 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.10815_10819del p.Lys3605AsnfsTer8 frameshift_variant De novo - Simplex 38356881 Qi Yang et al. (2024)
c.12898T>C p.Ser4300Pro missense_variant Familial Paternal Multiplex 34356069 Dhaliwal J et al. (2021)
c.11486G>A p.Gly3829Asp 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.14621G>A p.Arg4874Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3574del p.Val1192LeufsTer13 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8390dup p.Glu2798GlyfsTer11 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8543del p.Asn2848MetfsTer15 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.9915del p.Met3306TrpfsTer55 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.10374dup p.Pro3459ThrfsTer3 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.10588del p.Ser3530LeufsTer3 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.5667dup p.Arg1890ThrfsTer24 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.6910dup p.Met2304AsnfsTer8 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.12584del p.Pro4195HisfsTer23 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.6617del p.Pro2206LeufsTer33 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.5743dup p.Ser1915PhefsTer20 frameshift_variant Familial Maternal - 39013459 Dmitrijs Rots et al. (2024)
c.8390dup p.Glu2798GlyfsTer11 frameshift_variant Familial Paternal - 39013459 Dmitrijs Rots et al. (2024)
c.466_478del p.Thr156SerfsTer46 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.1378del p.Tyr460ThrfsTer35 frameshift_variant De novo - Multiplex 31981491 Satterstrom FK et al. (2020)
c.620C>G p.Ser207Cys missense_variant Familial Paternal Multiplex 39632905 Ashlesha Gogate et al. (2024)
c.6592_6593del p.Arg2198AlafsTer3 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.2816_2817del p.Ser939TyrfsTer10 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.5403_5404del p.Pro1802LysfsTer2 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8224_8225dup p.Asp2742GlufsTer9 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.5481_5485del p.Lys1827AsnfsTer17 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.14074G>A p.Gly4692Ser missense_variant Familial Maternal Multiplex 39632905 Ashlesha Gogate et al. (2024)
c.10724_10725dup p.Ile3576LeufsTer2 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.8849_8850del p.His2950ArgfsTer17 frameshift_variant Familial Paternal - 39013459 Dmitrijs Rots et al. (2024)
c.13107_13108dup p.Thr4370ArgfsTer11 frameshift_variant De novo - Simplex 39013459 Dmitrijs Rots et al. (2024)
c.6911_6912insA p.Met2304IlefsTer8 frameshift_variant Familial Maternal Simplex 38356881 Qi Yang et al. (2024)
c.11566_11567del p.Arg3856AspfsTer3 frameshift_variant Familial Maternal - 39013459 Dmitrijs Rots et al. (2024)
c.1759_1769del p.Gln587SerfsTer7 frameshift_variant De novo - Multiplex 38146907 Whitney Whitford et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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."

1/1/2021
1
icon
1

Score remained at 1

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
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
4/1/2020
1
icon
1

Score remained at 1

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
[Utility of clinical exome sequencing in a complex Emirati pediatric cohort2020]
1/1/2020
1
icon
1

Score remained at 1

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
[Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype.2020] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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
[Mutations in ASH1L confer susceptibility to Tourette syndrome.2019] [New Scoring Scheme]
1/1/2019
2S
icon
2S

Decreased from 2S to 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
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2017
2
icon
2S

Decreased from 2 to 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

Decreased from 2 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 < 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

Decreased from 2 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< 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
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [The Contribution of Mosaic Variants to Autism Spectrum Disorder.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
10/1/2016
2
icon
2

Decreased from 2 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

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

Decreased from 2 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

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016]
4/1/2015
2
icon
2

Decreased from 2 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

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
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