KMT2CLysine (K)-specific methyltransferase 2C
Autism Reports / Total Reports
26 / 40Rare Variants / Common Variants
157 / 0Aliases
KMT2C, HALR, MLL3Associated Syndromes
Kleefstra syndrome, Kleefstra syndrome 2, ASD, DD, ID, Kleefstra syndrome 2, DD, ID, ASD, Kleefstra syndrome 2Chromosome Band
7q36.1Associated Disorders
DD/NDD, ASDRelevance 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
SFARI Genomic Platforms
Reports related to KMT2C (40 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 | - |
Rare Variants (157)
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.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.3315A>G | p.Gln1105%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.5716C>T | p.Arg1906Ter | stop_gained | De novo | - | Simplex | 31673123 | Liu S , et al. (2019) | |
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.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.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.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.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.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
High Confidence, Syndromic
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe 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.
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
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.
4/1/2020
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.
1/1/2020
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.
10/1/2019
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.
1/1/2019
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.
10/1/2017
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
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).
4/1/2017
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
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
1/1/2016
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
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
10/1/2014
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]
ExAC Score
Score 1
Ranking 16/18225 scored genes
[Show Scoring Methodology]
Iossifov Probability Score
Score 0.984
Ranking 36/239 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.00047927143184048
Ranking 17/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 45
Ranking 41/461 scored genes
[Show Scoring Methodology]