SCN11A

protein-coding

sodium voltage-gated channel alpha subunit 11, the group of Sodium voltage-gated channel alpha subunits

Gene summary

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 highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

Previous symbols:

SCN12A

MANE transcript

NM_001349253.2

Inheritance

ClinVar variants

P:11U:981B:419

Top phenotype

Episodic pain syndrome, familial, 3; Neuropathy, hereditary sensory and autonomic, type VII

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr3:38,845,764-39,052,157

External References & Databases

Ensembl (ENSG00000168356)

Transcript & Mutation Effects

hg38 • Region Span ~206.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial episodic pain syndrome with predominantly lower limb involvementSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014247

Submitter: Orphanet

hereditary sensory and autonomic neuropathy type 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014244

Submitter: PanelApp Australia

familial episodic pain syndrome with predominantly lower limb involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014247

Submitter: Labcorp Genetics (formerly Invitae)

hereditary sensory and autonomic neuropathy type 7SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014244

Submitter: Orphanet

familial episodic pain syndrome with predominantly lower limb involvementDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014247

Submitter: G2P

hereditary sensory and autonomic neuropathy type 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014244

Submitter: Labcorp Genetics (formerly Invitae)

hereditary sensory and autonomic neuropathy type 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014244

Submitter: G2P

hereditary sensory and autonomic neuropathy type 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014244

Submitter: ClinGen

The gene SCN11A encodes the voltage-gated sodium channel Nav1.9 that was first discovered to be expressed in sensory neurons in 1998 (PMID: 9671787). Together with other voltage-gated sodium channel genes (SCN9A, SCN10A), likewise associated with hereditary neuropathic pain syndromes, it is responsible for the generation of action potentials in nociceptive nerve fibers (PMID: 27556810). In 2013, Leipold et al. (PMID: 24036948) described two families with the same de-novo SCN11A missense variant in association with congenital insensitivity to pain. Both affected individuals showed severe self-mutilation and autonomic disturbances. This phenotype was reproduced in patients with the same (PMIDs: 30395542, 25118027) and two different (PMIDs: 28289907, 26746779) SCN11A missense variants, all located in the terminal segment of one of the transmembrane domains (S6) constituting the pore-forming part of the sodium channel (PMIDs: 32601768, 28289907). By patch-clamp analysis, variants were shown to results in a prominent gain-of-function phenotype mediated by a leftward shift in channel activation and deactivation kinetics as well as by a slow- down in channel inactivation. A reduced density of spontaneous synaptic events in mouse dorsal horn neurons from a respective mouse model was observed (PMID: 24036948). In a heterozygous knock-in mouse model, the patient phenotype was reproduced showing non-healing wounds, increased amounts of scratch-bouts, and reduced grip-strength (PMIDs: 24036948, 32817686). In parallel, SCN11A has also been reported in association with an autosomal dominant neuropathic pain disorder described as recurrent episodes of severe distal limb and facial pain responding to NSAIDs and being aggravated by cold. Heterozygous missense mutations were found to segregate in large families (PMIDs: 24207120, 28298626, 30046661). On functional level, the variants increased current densities, but did not change the channel’s activation or deactivation thresholds (PMIDs: 24207120). In a heterozygous knock-in mouse model, the phenotype reproduced the phenomenon of cold-aggravated allodynia (PMID: 32970203). We therefore conclude that heterozygous missense mutations in SCN11A can cause both loss and gain of pain, depending on the respective consequences on cellular level. In other neuropathic pain disorder such as small fiber neuropathies, screening studies revealed the presence of SCN11A variants in several unrelated cases (PMID: 24776970). Despite causing a gain of channel function in voltage-clamp analyses, these variants show a variable allele frequency in control populations. It is therefore unclear to date, to what extent they constitute risk factors or contribute to the phenotype. In summary, the panel concludes that the gene disease relationship for SCN11A and autosomal dominant hereditary sensory and autonomic neuropathy is definitive. Of note, yet no clear pathological or electrophysiological signs of neuropathy have been reported in these pain perception disorders. Considering the expression in nociceptive sensory neurons and their expected dysfunction, however, the panel decided to call this disease “neuropathy”.

sodium channelopathy-related small fiber neuropathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017629

Submitter: Orphanet

Clinical Genomic Database (CGD)

Episodic pain syndrome, familial, 3; Neuropathy, hereditary sensory and autonomic, type VIIAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The pain has been reported as responsive to oral anti-inflammatory analgesics; Congenital insensitivity to pain can result in injuries and infections

Refs: 24036948; 24207120; 24776970; 25118027

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN11A variants in ClinVar

12 Conditions Cataloged

Hereditary sensory and autonomic neuropathy type 7Total: 1366

Familial episodic pain syndrome with predominantly lower limb involvementTotal: 1363

Inborn genetic diseasesTotal: 403

not providedTotal: 312

SCN11A-related disorderTotal: 222

not specifiedTotal: 129

Charcot-Marie-Tooth diseaseTotal: 9

Sensory neuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001349253.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			18 clinvar	300 clinvar	9 clinvar	327
missense	4 clinvar	6 clinvar	850 clinvar	104 clinvar	4 clinvar	968
nonsense		1 clinvar	36 clinvar	1 clinvar		38
start loss			1 clinvar			1
frameshift			52 clinvar	1 clinvar		53
splice donor/acceptor (+/-2bp)			24 clinvar			24
Total	4	7	981	406	13	1411

Highest pathogenic variant AF is 0.000022574413

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001349253.2	RefSeq	NP_001336182.1	26	MANE Select
ENST00000302328.9	Ensembl	ENSP00000307599.3	26	MANE Select
NM_014139.3	RefSeq	NP_054858.2	26	Standard
ENST00000444237.2	Ensembl	ENSP00000408028.2	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
Phase 0 - rapid depolarisation
Cardiac conduction
Muscle contraction
Interaction between L1 and Ankyrins

Biological Process

sodium ion transport
neuronal action potential
regulation of ion transmembrane transport
sodium ion transmembrane transport
response to drug

Molecular Function

voltage-gated ion channel activity
voltage-gated sodium channel activity

Cellular Component

voltage-gated sodium channel complex
plasma membrane
axon
C-fiber
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302328
Coding exons: 26
Length: 104793
Individuals with no LoFs: 125517
Homozygous LoFs: 0
Heterozygous LoFs: 231
Defined: 125748
p: 0.000919

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.964	881	965	0.913	0.0000517	11927
Missense (PolyPhen)		324	422.06	0.76765		5339
Synonymous	-0.249	350	344	1.02	0.0000186	3317
Loss of Function	2.84	53	80.5	0.659	0.00000451	933

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00086	0.00086	rare
Latino/Admixed American	0.0018	0.0017	notable
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00039	0.00038	rare
Finnish	0.00060	0.00060	rare
European (Non-Finnish)	0.0011	0.00098	notable
South Asian	0.00085	0.00059	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein 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 sodium ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant sodium channel isoform. Also involved, with the contribution of the receptor tyrosine kinase NTRK2, in rapid BDNF-evoked neuronal depolarization. {ECO:0000269|PubMed:10580103, ECO:0000269|PubMed:12384689}.;
Disease: DISEASE: Neuropathy, hereditary sensory and autonomic, 7 (HSAN7) [MIM:615548]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN7 is characterized by congenital inability to experience pain resulting in self-mutilations, slow-healing wounds, and multiple painless fractures. mild muscle weakness, delayed motor development, slightly reduced motor and sensory nerve conduction velocities, hyperhidrosis and gastrointestinal dysfunction. {ECO:0000269|PubMed:24036948, ECO:0000269|PubMed:26645915}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Episodic pain syndrome, familial, 3 (FEPS3) [MIM:615552]: An autosomal dominant neurologic disorder characterized by paroxysmal pain mainly affecting the distal lower extremities and occasionally the upper body, especially the joints of fingers and arms. The pain is exacerbated with fatigue. {ECO:0000269|PubMed:24207120, ECO:0000269|PubMed:24776970, ECO:0000269|PubMed:25791876, ECO:0000269|PubMed:27224030}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0774
RVIS EVS: -1.82
RVIS percentile EVS: 2.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.135

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium