KCNQ3potassium voltage-gated channel subfamily Q member 3
Autism Reports / Total Reports
7 / 11Rare Variants / Common Variants
36 / 1Aliases
KCNQ3, BFNC2, EBN2, KV7.3Associated Syndromes
-Genetic Category
Rare Single Gene Mutation, Genetic AssociationChromosome Band
8q24.22Associated Disorders
DD/NDD, ASD, ADHD, IDRelevance to Autism
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish boy diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013).
Molecular Function
This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2).
Reports related to KCNQ3 (11 Reports)
# | Type | Title | Author, Year | Autism Report | Associated Disorders |
---|---|---|---|---|---|
1 | Positive Association | Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs. | Zhang P , et al. (2010) | No | - |
2 | Primary | Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders. | Gilling M , et al. (2013) | Yes | - |
3 | Positive Association | De novo mutations in epileptic encephalopathies. | Epi4K Consortium , et al. (2013) | No | IS, LGS, DD, ID, ASD, ADHD |
4 | Support | Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. | Toma C , et al. (2013) | Yes | - |
5 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism. | De Rubeis S , et al. (2014) | Yes | - |
6 | Support | Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. | Geisheker MR , et al. (2017) | Yes | - |
7 | Support | Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v... | Lecoquierre F , et al. (2019) | No | - |
8 | Recent Recommendation | Autism and developmental disability caused by KCNQ3 gain-of-function variants. | Sands TT , et al. (2019) | Yes | Abnormal EEG, absent speech |
9 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
10 | Support | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders | Wang T et al. (2020) | Yes | ID |
11 | Highly Cited | A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. | Charlier C , et al. (1998) | No | - |
Rare Variants (36)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | translocation | De novo | NA | Simplex | 23596459 | Gilling M , et al. (2013) | |
c.1090C>T | p.Arg364Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1411C>T | p.Arg471Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1850G>C | p.Ser617Thr | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1918G>A | p.Val640Met | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.2561C>T | p.Ser854Leu | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.569G>A | p.Arg190Gln | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.656G>A | p.Gly219Asp | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.680G>A | p.Arg227Gln | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.688C>T | p.Arg230Cys | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.689G>A | p.Arg230His | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.1123G>A | p.Ala375Thr | missense_variant | De novo | NA | - | 33004838 | Wang T et al. (2020) | |
c.927G>A | p.Trp309Ter | stop_gained | Familial | Maternal | - | 33004838 | Wang T et al. (2020) | |
c.328C>T | p.Arg110Cys | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.329G>A | p.Arg110His | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.680G>A | p.Arg227Gln | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.688C>A | p.Arg230Ser | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.688C>T | p.Arg230Cys | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.689G>A | p.Arg230His | missense_variant | De novo | NA | - | 31177578 | Sands TT , et al. (2019) | |
c.320G>A | p.Arg107Gln | missense_variant | Unknown | - | - | 28628100 | Geisheker MR , et al. (2017) | |
c.328C>T | p.Arg110Cys | missense_variant | Unknown | - | - | 28628100 | Geisheker MR , et al. (2017) | |
c.706C>T | p.Arg236Cys | missense_variant | De novo | NA | - | 25363760 | De Rubeis S , et al. (2014) | |
c.296G>A | p.Gly99Asp | missense_variant | De novo | NA | - | 28628100 | Geisheker MR , et al. (2017) | |
c.707G>A | p.Arg236His | missense_variant | Familial | Paternal | - | 33004838 | Wang T et al. (2020) | |
c.688C>T | p.Arg230Cys | missense_variant | De novo | NA | - | 31036916 | Lecoquierre F , et al. (2019) | |
c.689G>A | p.Arg230His | missense_variant | Familial | Maternal | - | 31177578 | Sands TT , et al. (2019) | |
c.1582C>T | p.Arg528Cys | missense_variant | Unknown | Not maternal | - | 33004838 | Wang T et al. (2020) | |
c.688C>T | p.Arg230Cys | missense_variant | De novo | NA | - | 23934111 | Epi4K Consortium , et al. (2013) | |
c.328C>T | p.Arg110Cys | missense_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.329G>A | p.Arg110His | missense_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.329G>T | p.Arg110Leu | missense_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.439G>A | p.Glu147Lys | missense_variant | Familial | Paternal | Multiplex | 33004838 | Wang T et al. (2020) | |
c.1964C>T | p.Thr655Met | missense_variant | Familial | Maternal | Multiplex | 23999528 | Toma C , et al. (2013) | |
c.1720C>T | p.Pro574Ser | missense_variant | Familial | Paternal | Unknown | 23596459 | Gilling M , et al. (2013) | |
c.929G>T | p.Gly310Val | missense_variant | Familial | - | Multi-generational | 9425900 | Charlier C , et al. (1998) | |
c.1720C>T | p.Pro574Ser | missense_variant | Familial | Maternal | Multi-generational | 23596459 | Gilling M , et al. (2013) |
Common Variants (1)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | C/T | upstream_gene_variant | - | - | - | 21176025 | Zhang P , et al. (2010) |
SFARI Gene score
High Confidence


A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.
Score Delta: Score remained at 2
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.
10/1/2020

Score remained at 2
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.
1/1/2020

Score remained at 2
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.
10/1/2019

Score remained at 2
New Scoring Scheme
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.
Reports Added
[New Scoring Scheme]7/1/2019

Decreased from 3 to 2
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.
7/1/2018

Decreased from 4.4 + acc2 to 3
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).
4/1/2018

Increased from 3 to 4.4 + acc2
Description
3
7/1/2017

Increased from 3 to 3
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).
1/1/2016

Increased from 3 to 3
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).
Reports Added
[Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders.2013] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs.2010] [A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.1998] [De novo mutations in epileptic encephalopathies.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]7/1/2015

Increased from to 3
Description
A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).
Krishnan Probability Score
Score 0.57200873874368
Ranking 729/25841 scored genes
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ExAC Score
Score 0.98560429367235
Ranking 1967/18225 scored genes
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Sanders TADA Score
Score 0.68415932139871
Ranking 1063/18665 scored genes
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Larsen Cumulative Evidence Score
Score 19
Ranking 108/461 scored genes
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Zhang D Score
Score 0.2521903694078
Ranking 3457/20870 scored genes
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