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SCN4A

sodium voltage-gated channel alpha subunit 4, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 17:63938553-63972918

Previous symbols: [ "HYKPP" ]

Links

ENSG00000007314 ∙ NCBI:6329 ∙ OMIM:603967 ∙ HGNC:10591 ∙ Uniprot:P35499 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • hypokalemic periodic paralysis, type 1 (Definitive), mode of inheritance: AD
  • hyperkalemic periodic paralysis (Definitive), mode of inheritance: AD
  • paramyotonia congenita of Von Eulenburg (Definitive), mode of inheritance: AD
  • congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
  • hypokalemic periodic paralysis, type 2 (Strong), mode of inheritance: AD
  • hyperkalemic periodic paralysis (Strong), mode of inheritance: AD
  • paramyotonia congenita of Von Eulenburg (Strong), mode of inheritance: AD
  • congenital myopathy (Strong), mode of inheritance: AR
  • congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
  • paramyotonia congenita of Von Eulenburg (Definitive), mode of inheritance: AD
  • paramyotonia congenita of Von Eulenburg (Supportive), mode of inheritance: AD
  • hypokalemic periodic paralysis (Supportive), mode of inheritance: AD
  • hyperkalemic periodic paralysis (Supportive), mode of inheritance: AD
  • postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
  • myotonia fluctuans (Supportive), mode of inheritance: AD
  • myotonia permanens (Supportive), mode of inheritance: AD
  • acetazolamide-responsive myotonia (Supportive), mode of inheritance: AD
  • congenital myasthenic syndrome 16 (Strong), mode of inheritance: AR
  • SCN4A-related myopathy, autosomal recessive (Definitive), mode of inheritance: AR
  • potassium-aggravated myotonia (Strong), mode of inheritance: AD
  • congenital myasthenic syndrome 16 (Limited), mode of inheritance: AR
  • hypokalemic periodic paralysis, type 2 (Strong), mode of inheritance: AD
  • hyperkalemic periodic paralysis (Strong), mode of inheritance: AD
  • paramyotonia congenita of Von Eulenburg (Strong), mode of inheritance: AD
  • congenital myopathy 22A, classic (Strong), mode of inheritance: AR
  • SCN4A-related myopathy, autosomal recessive (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Paramyotonia congenita; Hyperkalemic periodic paralysis, type 2; Hypokalemic periodic paralysis, type 2; Normokalemic potassium-sensitive periodic paralysis; Malignant hyperthermia, susceptibility to; Myasthenic syndrome, congenital, 16; Myotonia, potassium-aggravatedAD/ARCardiovascular; Musculoskeletal; Neurologic; PharmacogenomicIn hypokalemic disease, treatment, such as potassium supplementation can be effective; Acetazolamide treatment is beneficial in the majority (including with normokalemic and hyperkalemic disease), but in a lower proportion of variant-negative patients; Individuals can have cardiac complications, including sudden cardiac death; In Paramyotonia congenita, medications (eg, mexilitene, carbamazepine, phenytoin) may be effect in some individuals, and avoidance and specific preciptating circumstances may be beneficial; Myotonia, potassium-aggravated can be aggravated by potassium and fasting, and effectively treated with medications (eg, acetazolamide, carbamazepine, mexilitene); In Malignant hyperthermia, early diagnosis, discontinuation of potent inhalation agents/succinylcholine, treatment of metabolic abnormalities, and administration of dantrolene sodium intravenously are essential to treat acute MH; In Myasthenic syndrome, congenital, pyridostigmine can improve endurance; Acetazolamide can prevent further attacks of respiratory and bulbar weaknessCardiovascular; Craniofacial; Musculoskeletal; Neurologic13544644; 13758355; 13963901; 13946346; 14090531; 5828532; 14237771; 673408; 852462; 4022357; 3587272; 2396930; 1654742; 1310898; 1338909; 1316765; 8424309; 8385748; 8242056; 8308722; 8058156; 7741283; 9131651; 9131654; 10599760; 10369308; 10930446; 10727489; 12933953; 12766226; 15534250; 15557532; 15596759; 15642860; 16832098; 16786525; 17998485; 18203179; 19015492; 19015483; 18337100; 19118277; 20237798; 20301512; 20301669; 20713951; 21220685; 22617007; 23460624; 23516313; 23771340; 23801527; 23958773; 24082935; 25707578; 26659129; 26700687; 28262468; 36090556
Clinically, allelic conditions have been divided into different forms of the disorder: paramyotonia, potassium-aggravated myotonia, and periodic paralysis; Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN4A gene.

  • Familial hyperkalemic periodic paralysis (1466 variants)
  • not provided (654 variants)
  • Paramyotonia congenita of Von Eulenburg (229 variants)
  • Hypokalemic periodic paralysis, type 2 (218 variants)
  • Potassium-aggravated myotonia (214 variants)
  • Congenital myasthenic syndrome 16 (214 variants)
  • 6 conditions (214 variants)
  • not specified (149 variants)
  • Inborn genetic diseases (80 variants)
  • SCN4A-related condition (17 variants)
  • SCN4A-related non-dystrophic myotonia (10 variants)
  • Hypokalemic periodic paralysis, type 2;Potassium-aggravated myotonia;Paramyotonia congenita of Von Eulenburg;Familial hyperkalemic periodic paralysis;Congenital myasthenic syndrome 16 (8 variants)
  • Hypokalemic periodic paralysis (6 variants)
  • Hypokalemic periodic paralysis, type 1 (5 variants)
  • Congenital Myasthenic Syndrome, Recessive (5 variants)
  • Congenital myopathy 22A, classic (4 variants)
  • Paramyotonia congenita/hyperkalemic periodic paralysis (3 variants)
  • Congenital myopathy 22B, severe fetal (3 variants)
  • Potassium-aggravated myotonia;Paramyotonia congenita of Von Eulenburg;Hypokalemic periodic paralysis, type 2;Familial hyperkalemic periodic paralysis;Congenital myasthenic syndrome 16 (3 variants)
  • SCN4A-Related Disorders (3 variants)
  • Normokalemic periodic paralysis, potassium-sensitive (3 variants)
  • Hypokalemic periodic paralysis, type 2;Potassium-aggravated myotonia;Familial hyperkalemic periodic paralysis;Congenital myasthenic syndrome 16;Paramyotonia congenita of Von Eulenburg (2 variants)
  • Microcephaly (2 variants)
  • See cases (2 variants)
  • Acetazolamide-responsive myotonia (2 variants)
  • Long QT syndrome (2 variants)
  • - (2 variants)
  • Myotonia fluctuans (2 variants)
  • Myopathy (2 variants)
  • Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (1 variants)
  • SCN4A-related disorder (1 variants)
  • Batten-Turner congenital myopathy (1 variants)
  • SUDDEN INFANT DEATH SYNDROME (1 variants)
  • Joubert syndrome 17 (1 variants)
  • Myotonia congenita, atypical, acetazolamide-responsive (1 variants)
  • Hypokalemic periodic paralysis, type 2;Familial hyperkalemic periodic paralysis;Paramyotonia congenita of Von Eulenburg;Potassium-aggravated myotonia (1 variants)
  • Myotonia;Handgrip myotonia (1 variants)
  • Sotos syndrome (1 variants)
  • Focal-onset seizure (1 variants)
  • Congenital myasthenic syndrome (1 variants)
  • Paramyotonia congenita/myotonia congenita (1 variants)
  • Congenital myopathy (1 variants)
  • Myotonia permanens (1 variants)
  • Hypokalemic periodic paralysis, type 2;Congenital myasthenic syndrome 16;Familial hyperkalemic periodic paralysis;Paramyotonia congenita of Von Eulenburg;Potassium-aggravated myotonia (1 variants)
  • Myotonia;Muscle weakness (1 variants)
  • Paramyotonia congenita of Von Eulenburg;Hypokalemic periodic paralysis, type 2;Congenital myasthenic syndrome 16;Potassium-aggravated myotonia;Familial hyperkalemic periodic paralysis (1 variants)
  • Rhabdomyolysis (1 variants)
  • Hypokalemic periodic paralysis, type 2;Congenital myasthenic syndrome 16;Potassium-aggravated myotonia;Familial hyperkalemic periodic paralysis;Paramyotonia congenita of Von Eulenburg (1 variants)
  • Delayed gross motor development (1 variants)
  • Abnormality of the musculature (1 variants)
  • Hypokalemic periodic paralysis, type 2;Congenital myasthenic syndrome 16;Paramyotonia congenita of Von Eulenburg;Familial hyperkalemic periodic paralysis;Potassium-aggravated myotonia (1 variants)
  • Familial hyperkalemic periodic paralysis;Hypokalemic periodic paralysis, type 2 (1 variants)
  • SCN4A-related myopathy, autosomal recessive (1 variants)
  • Severe neonatal hypotonia improving with age (1 variants)
  • Limb pain;Muscle weakness;Pain;EMG: myotonic discharges;Distal sensory impairment (1 variants)
  • Potassium-aggravated myotonia;Paramyotonia congenita of Von Eulenburg;Hypokalemic periodic paralysis, type 2;Congenital myasthenic syndrome 16;Familial hyperkalemic periodic paralysis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN4A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
21
clinvar
325
clinvar
18
clinvar
 364
missense
43
clinvar
41
clinvar
795
clinvar
14
clinvar
5
clinvar
 898
nonsense
9
clinvar
3
clinvar
2
clinvar
 14
start loss
0
frameshift
9
clinvar
5
clinvar
2
clinvar
 16
inframe indel
1
clinvar
18
clinvar
 19
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
3
clinvar
 7
splice region
?
    Intron variants in splice region, excluding donor/acceptor (+/-2bp)
24
47
6
 77
non coding
?
    UTR, intron and other, non coding variants
33
clinvar
122
clinvar
81
clinvar
 236
Total 62 53 874 461 104

Highest pathogenic variant AF is 0.0000197

Variants in SCN4A

This is a list of pathogenic ClinVar variants found in the SCN4A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
17-63938560-G-A Hypokalemic periodic paralysis, type 2 • Hyperkalemic periodic paralysis • Paramyotonia congenita of Von Eulenburg • Congenital myasthenic syndrome 16 • Potassium-aggravated myotonia Uncertain significance (Jan 13, 2018)324463
17-63938601-C-T Congenital myasthenic syndrome 16 • Hyperkalemic periodic paralysis • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Hypokalemic periodic paralysis, type 2 Conflicting classifications of pathogenicity (Jan 12, 2018)889220
17-63938602-G-C Potassium-aggravated myotonia • Hyperkalemic periodic paralysis • Hypokalemic periodic paralysis, type 2 • Congenital myasthenic syndrome 16 • Paramyotonia congenita of Von Eulenburg Conflicting classifications of pathogenicity (Jan 13, 2018)324464
17-63938621-G-T Hyperkalemic periodic paralysis • Paramyotonia congenita of Von Eulenburg • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Congenital myasthenic syndrome 16 Conflicting classifications of pathogenicity (Jan 12, 2018)324465
17-63938686-G-C Hypokalemic periodic paralysis, type 2 • Hyperkalemic periodic paralysis • Potassium-aggravated myotonia • Paramyotonia congenita of Von Eulenburg • Congenital myasthenic syndrome 16 Uncertain significance (Jan 13, 2018)889900
17-63938699-C-T Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Congenital myasthenic syndrome 16 • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis Conflicting classifications of pathogenicity (Jan 13, 2018)324466
17-63938782-G-A Hypokalemic periodic paralysis, type 2 • Congenital myasthenic syndrome 16 • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis • Potassium-aggravated myotonia Benign/Likely benign (May 25, 2021)324467
17-63938855-G-A Congenital myasthenic syndrome 16 • Hypokalemic periodic paralysis, type 2 • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis Conflicting classifications of pathogenicity (Jan 13, 2018)324468
17-63938881-G-T Paramyotonia congenita of Von Eulenburg • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis • Congenital myasthenic syndrome 16 Uncertain significance (Jan 12, 2018)324469
17-63938884-T-C Hypokalemic periodic paralysis, type 2 • Paramyotonia congenita of Von Eulenburg • Congenital myasthenic syndrome 16 • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis Uncertain significance (Jan 12, 2018)324470
17-63938896-T-C Hyperkalemic periodic paralysis • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Paramyotonia congenita of Von Eulenburg • Congenital myasthenic syndrome 16 Uncertain significance (Jan 13, 2018)324471
17-63938943-T-C Paramyotonia congenita of Von Eulenburg • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis • Congenital myasthenic syndrome 16 Benign/Likely benign (Jan 12, 2018)324472
17-63939034-T-C Paramyotonia congenita of Von Eulenburg • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Congenital myasthenic syndrome 16 • Hyperkalemic periodic paralysis Benign (May 25, 2021)324473
17-63939075-G-C Benign (Aug 13, 2021)1304844
17-63939080-G-GCA Congenital Myasthenic Syndrome, Recessive • Hypokalemic periodic paralysis • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis Benign (May 14, 2021)324474
17-63939093-C-CAT Potassium-aggravated myotonia • Hypokalemic periodic paralysis • Congenital Myasthenic Syndrome, Recessive • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis Benign/Likely benign (Sep 18, 2021)324475
17-63939160-T-C Potassium-aggravated myotonia • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis • Hypokalemic periodic paralysis, type 2 • Congenital myasthenic syndrome 16 Benign (Jan 12, 2018)324476
17-63939172-T-C Congenital myasthenic syndrome 16 • Hypokalemic periodic paralysis, type 2 • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis Uncertain significance (Jan 12, 2018)889337
17-63939199-A-C Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis • Hypokalemic periodic paralysis, type 2 • Congenital myasthenic syndrome 16 • Potassium-aggravated myotonia Uncertain significance (Jan 13, 2018)324477
17-63939266-C-A Paramyotonia congenita of Von Eulenburg • Congenital myasthenic syndrome 16 • Hyperkalemic periodic paralysis • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia Uncertain significance (Jan 12, 2018)890024
17-63939274-G-A Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis • Congenital myasthenic syndrome 16 Uncertain significance (Jan 13, 2018)890025
17-63939344-A-G Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia • Paramyotonia congenita of Von Eulenburg • Hyperkalemic periodic paralysis • Congenital myasthenic syndrome 16 Benign (May 16, 2021)324478
17-63939367-C-CACACATATAT Hypokalemic periodic paralysis • Congenital Myasthenic Syndrome, Recessive • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Hyperkalemic periodic paralysis Benign (May 15, 2021)324479
17-63939403-C-G Hypokalemic periodic paralysis, type 2 • Paramyotonia congenita of Von Eulenburg • Potassium-aggravated myotonia • Congenital myasthenic syndrome 16 • Hyperkalemic periodic paralysis Benign/Likely benign (May 15, 2021)324480
17-63939414-T-C Hyperkalemic periodic paralysis • Congenital myasthenic syndrome 16 • Paramyotonia congenita of Von Eulenburg • Hypokalemic periodic paralysis, type 2 • Potassium-aggravated myotonia Benign (May 16, 2021)324481

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SCN4Aprotein_codingprotein_codingENST00000435607 2434365
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.01290.98712543603101257460.00123
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.569771.12e+30.8690.000070712161
Missense in Polyphen327465.980.701755051
Synonymous0.1054804830.9940.00003553468
Loss of Function5.911973.70.2580.00000357806

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.01020.00858
Ashkenazi Jewish0.0006560.000595
East Asian0.0008550.000653
Finnish0.0005820.000554
European (Non-Finnish)0.0007680.000703
Middle Eastern0.0008550.000653
South Asian0.001350.00118
Other0.0007820.000652

dbNSFP

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 Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. {ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:16890191}.;
Disease
DISEASE: Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. {ECO:0000269|PubMed:10369308, ECO:0000269|PubMed:10727489, ECO:0000269|PubMed:1310898, ECO:0000269|PubMed:1316765, ECO:0000269|PubMed:1338909, ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:15790667, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:18166706, ECO:0000269|PubMed:18690054, ECO:0000269|PubMed:19077043, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8242056, ECO:0000269|PubMed:8308722, ECO:0000269|PubMed:8388676, ECO:0000269|PubMed:8580427}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis hypokalemic 2 (HOKPP2) [MIM:613345]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:10599760, ECO:0000269|PubMed:10851391, ECO:0000269|PubMed:10944223, ECO:0000269|PubMed:11558801, ECO:0000269|PubMed:11591859, ECO:0000269|PubMed:16890191, ECO:0000269|PubMed:17898326, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:20522878, ECO:0000269|PubMed:21043388, ECO:0000269|PubMed:24549961}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis hyperkalemic (HYPP) [MIM:170500]: An autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients. {ECO:0000269|PubMed:1659668, ECO:0000269|PubMed:1659948, ECO:0000269|PubMed:20076800}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Periodic paralysis normokalemic (NKPP) [MIM:170500]: A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. {ECO:0000269|PubMed:15596759, ECO:0000269|PubMed:18046642, ECO:0000269|PubMed:20522878}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myotonia SCN4A-related (MYOSCN4A) [MIM:608390]: A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. Myotonia SCN4A- related includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise. {ECO:0000269|PubMed:10218481, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:16832098, ECO:0000269|PubMed:17212350, ECO:0000269|PubMed:17998485, ECO:0000269|PubMed:18203179, ECO:0000269|PubMed:18337100, ECO:0000269|PubMed:19015483, ECO:0000269|PubMed:19347921, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:27653901, ECO:0000269|PubMed:8058156, ECO:0000269|PubMed:9392583}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 16 (CMS16) [MIM:614198]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS16 is characterized by fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid-elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation. {ECO:0000269|PubMed:12766226, ECO:0000269|PubMed:25707578, ECO:0000269|PubMed:26659129}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=SCN4A mutations are the cause of an autosomal recessive neuromuscular disorder characterized by severe fetal hypokinesia, neonatal hypotonia and congenital myopathy of variable severity. The most severe clinical features include reduced or absent fetal movements, in-utero upper and lower limb contractures, talipes and hydrops, and intrauterine or early postnatal death. Mildly affected patients present with generalized hypotonia and weakness at birth or within the first few days of life, mild-to-moderate facial muscle weakness without ptosis, significant early respiratory and feeding difficulties, and skeletal abnormalities of the spine and palate. Symptoms improve over time in patients who survive infancy, resulting in gain of muscle strength and motor skills and concomitant resolution of early respiratory and feeding difficulties. In contrast to other SCN4A-related channelopathies, affected individuals manifest in- utero or neonatal onset of permanent muscle weakness, rather than later-onset episodic muscle weakness. {ECO:0000269|PubMed:26700687}.;
Pathway
Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance (Consensus)

Recessive Scores

pRec
0.338

Intolerance Scores

loftool
0.00572
rvis_EVS
-0.75
rvis_percentile_EVS
13.68

Haploinsufficiency Scores

pHI
0.132
hipred
Y
hipred_score
0.554
ghis
0.512

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
gene_indispensability_pred
E
gene_indispensability_score
0.794

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Scn4a
Phenotype
muscle phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hearing/vestibular/ear phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan);

Zebrafish Information Network

Gene name
scn4aa
Affected structure
skeletal muscle
Phenotype tag
abnormal
Phenotype quality
disorganized

Gene ontology

Biological process
sodium ion transport;muscle contraction;neuronal action potential;regulation of ion transmembrane transport;sodium ion transmembrane transport;membrane depolarization during action potential
Cellular component
voltage-gated sodium channel complex;plasma membrane;integral component of plasma membrane;axon
Molecular function
voltage-gated ion channel activity;voltage-gated sodium channel activity