Human Gene Module / Chromosome 2 / SCN3A

SCN3Asodium voltage-gated channel alpha subunit 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
10 / 13
Rare Variants / Common Variants
16 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
2q24.3
Associated Disorders
-
Relevance to Autism

Whole genome and/or whole exome sequencing of 435 individuals in 116 ASD families in Viggiano et al., 2024 identified a de novo nonsense variant in the SCN3A gene in a 12-year-old male ASD proband who also presented with language consisting of single words, a normal IQ, delivery by C-section following an uneventful dichorionic diamniotic pregnancy, mild kyphosis, bilateral fifth finger clinodactyly, and bilateral 2-3 toe syndactyly; this variant was not observed in his dizygotic twin brother, who was also diagnosed with ASD. De novo missense variants in the SCN3A gene, several of which were predicted to be damaging by in silico algorithms, have previously been reported in ASD probands from the Simons Simplex Collection and the SPARK cohort (Iossifov et al., 2014; Zhou et al., 2022; Trost et al., 2022). Inherited loss-of-function and missense variants have also been identified in ASD probands (Ruzzo et al., 2019; Hu et al., 2023). Autistic features were reported in one of two individuals presenting with developmental delay and refractory epilepsy and carrying de novo SCN3A variants in Inuzuka et al., 2020. Autism spectrum disorder or autistic features have also been previously observed in individuals with heterozygous deletions affecting the SCN2A and SCN3A genes (Celle et al., 2013; Chong et al., 2018; Nickel et al., 2018).

Molecular Function

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Heterozygous mutations in this gene are responsible for developmental and epileptic encephalopathy 62 (DEE62; OMIM 617938) and familial focal epilepsy with variable foci 4 (FFEVF4; OMIM 617935).

External Links
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Reports related to SCN3A (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Celle ME , et al. (2013) No Autistic features
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Pin Fee Chong et al. (2018) Yes -
4 Support - Kathrin Nickel et al. (2018) Yes -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support - Luciana Midori Inuzuka et al. (2020) No Autistic features
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Trost B et al. (2022) Yes -
10 Support - Hu C et al. (2023) Yes -
11 Primary - Marta Viggiano et al. (2024) Yes -
12 Support - Karen Lob et al. () Yes DD, epilepsy/seizures
13 Support - Hosneara Akter et al. () No ASD, epilepsy/seizures
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 29929112 Pin Fee Chong et al. (2018)
- - copy_number_loss Unknown - Unknown 24080482 Celle ME , et al. (2013)
- - copy_number_loss De novo - Multiplex 30071822 Kathrin Nickel et al. (2018)
c.941A>G p.Asn314Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4862G>A p.Arg1621Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2645T>A p.Leu882Gln missense_variant De novo - - 36368308 Trost B et al. (2022)
c.5027A>C p.Asn1676Thr missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.1301C>A p.Thr434Asn missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.5707T>A p.Ser1903Thr missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.1593C>T p.Ser531= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.5696A>T p.Gln1899Leu missense_variant Familial Maternal - 39136901 Karen Lob et al. ()
c.1267G>A p.Val423Met missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4888C>T p.Arg1630Ter stop_gained De novo - Multiplex 38519481 Marta Viggiano et al. (2024)
c.301C>T p.Arg101Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5295G>A p.Met1765Ile missense_variant De novo - - 31677917 Luciana Midori Inuzuka et al. (2020)
c.2803_2805del p.Leu935del inframe_deletion De novo - - 31677917 Luciana Midori Inuzuka et al. (2020)
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.

7/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.57191615366268

Ranking 737/25841 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 0.99999999284726

Ranking 130/18225 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
Sanders TADA Score

Score 0.9181011193985

Ranking 8763/18665 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 0.32535614614911

Ranking 2350/20870 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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