Human Gene Module / Chromosome 2 / SCN9A

SCN9Asodium voltage-gated channel alpha subunit 9

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
25 / 0
Aliases
SCN9A, ETHA,  FEB3B,  GEFSP7,  HSAN2D,  NE-NA,  NENA,  Nav1.7,  PN1,  SFNP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
2q24.3
Associated Disorders
-
Relevance to Autism

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016).

Molecular Function

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. Plays a role in pain mechanisms, especially in the development of inflammatory pain.

Reports related to SCN9A (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. Singh NA , et al. (2009) No Febrile seizures
2 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
3 Support Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder. Allen NM , et al. (2016) No -
4 Primary Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism. Rubinstein M , et al. (2016) Yes -
5 Support Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Chen XS , et al. (2017) No -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1921A>T p.Asn641Tyr missense_variant Familial - Multi-generational 19763161 Singh NA , et al. (2009)
c.612_613insTT p.Val205fs frameshift_variant Familial Paternal Multiplex 25621899 Yuen RK , et al. (2015)
c.1964A>G p.Lys655Arg missense_variant Familial Maternal - 27504264 Allen NM , et al. (2016)
c.3428G>T p.Cys1143Phe missense_variant Familial Unknown Extended multiplex 27956748 Rubinstein M , et al. (2016)
c.3523T>A p.Tyr1175Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3449G>A p.Trp1150Ter stop_gained Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3369G>T p.Leu1123Phe missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3328C>T p.Arg1110Trp missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3136G>A p.Asp1046Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3092C>T p.Thr1031Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.[2794A>C;2971G>T] p.[Met932Leu;Val991Leu] missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4612C>T p.Trp1538Arg missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4282G>A p.Val1428Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.4040G>A p.Arg1347Glu missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.3799C>G p.Leu1267Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2391G>A p.Trp797Ter stop_gained Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2271G>A p.Met757Ile missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.2215A>G p.Ile739Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1940A>T p.Glu647Val missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1846G>A p.Gly616Arg missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1469G>A p.Ser490Asn missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.1115G>A p.Arg372His missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.684C>G p.Ile228Met missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.554G>A p.Arg185His missense_variant Familial Unknown Unknown 27956748 Rubinstein M , et al. (2016)
c.[3799C>G];[3734A>G] p.[Leu1267Val];[Asn1245Ser] missense_variant;missense_variant Familial - Simplex 28440294 Chen XS , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016). Inherited variants in SCN9A had previously been identified in both affected siblings of a multiplex ASD family (Yuen et al., 2015), as well as in a male proband with atypical benign partial epilepsy (ABPE) of childhood and a diagnosis of PDD-NOS (Allen et al., 2016). Singh et al., 2009 identified a functional missense variant in SCN9A that segregated with febrile seizures in a large Utah family with 21 affected members; in the same report, it was suggested that SCN9A could act as a potential modifier of Dravet syndrome.

2

Strong Candidate

See all Category 2 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.

04-01-2017
2

Initial score established: 2

Description

Whole-exome sequencing of five families in which second- and third-degree relatives were affected with autism identified a novel private missense variant (p.Cys1143Phe) in the second intracellular loop of the Nav1.7 sodium channel (encoded by the SCN9A gene) that exhibited partial loss-of-function effects. An excess of rare missense variants in the same intracellular loop was subsequently observed in a case-control variant-burden study of 1004 familial ASD cases and 1127 controls (29 in cases vs. 2 in controls; P=5.1E-07), with one of the variants (p.Met932Leu/Val991Leu) also showing functional effects (Rubinstein et al., 2016). Inherited variants in SCN9A had previously been identified in both affected siblings of a multiplex ASD family (Yuen et al., 2015), as well as in a male proband with atypical benign partial epilepsy (ABPE) of childhood and a diagnosis of PDD-NOS (Allen et al., 2016). Singh et al., 2009 identified a functional missense variant in SCN9A that segregated with febrile seizures in a large Utah family with 21 affected members; in the same report, it was suggested that SCN9A could act as a potential modifier of Dravet syndrome.

CNVs associated with SCN9A(1 CNVs)
2q24.3 10 Deletion 21  /  93
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