Human Gene Module / Chromosome 1 / KCNA3

KCNA3potassium voltage-gated channel subfamily A member 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
14 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1p13.3
Associated Disorders
-
Relevance to Autism

Soldovieri et al., 2023 described 14 individuals carrying de novo missense variants in the KCNA3 gene, most of whom presented with a developmental and epileptic encephalopathy characterized by speech delay with or without motor delay, intellectual disability, epilepsy, and autism spectrum disorder; functional analysis of Kv1.3 channels carrying each missense variant revealed heterogeneous functional changes, ranging from loss-of-function effects with or without dominant negative effects to mixed loss- and gain-of-function effects. A de novo nonsense variant in the KCNA3 gene had previously been reported in an ASD proband from the SPARK cohort (Zhou et al., 2022).

Molecular Function

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T-cell proliferation and activation.

External Links
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Reports related to KCNA3 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Zhou X et al. (2022) Yes -
2 Primary - Maria Virginia Soldovieri et al. (2024) Yes Epilepsy/seizures
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.436G>T p.Glu146Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.32C>G p.Pro11Arg missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1292T>A p.Ile431Asn missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1328C>T p.Thr443Ile missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1378G>A p.Val460Met missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1403G>T p.Gly468Val missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1432G>A p.Val478Met missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1574G>A p.Ser525Asn missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
c.1363A>G p.Ile455Val missense_variant De novo - Simplex 37964487 Maria Virginia Soldovieri et al. (2024)
c.1402G>C p.Gly468Arg missense_variant Unknown - Simplex 37964487 Maria Virginia Soldovieri et al. (2024)
c.1430C>A p.Pro477His missense_variant Unknown - Simplex 37964487 Maria Virginia Soldovieri et al. (2024)
c.1070C>T p.Ala357Val missense_variant De novo - Multiplex 37964487 Maria Virginia Soldovieri et al. (2024)
c.1081G>A p.Ala361Thr missense_variant De novo - Multiplex 37964487 Maria Virginia Soldovieri et al. (2024)
c.1402_1403delinsTT p.Gly468Phe missense_variant De novo - - 37964487 Maria Virginia Soldovieri et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49608378753754

Ranking 2692/25841 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
Sanders TADA Score

Score 0.93991142055058

Ranking 14378/18665 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
Zhang D Score

Score 0.057312310852454

Ranking 7045/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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