Skeletal muscle channelopathy: genes and variants

Genes linked to Skeletal muscle channelopathy

• CLCN1: Chloride channel protein 1

  Its chloride conductance stabilizes the resting membrane potential of skeletal muscle and prevents repetitive firing after contraction. Loss-of-function variants cause myotonia congenita, with delayed muscle relaxation and stiffness.

  11 disease-causing and 3 uncertain variants in CLCN1 are linked to Skeletal muscle channelopathy.

• SCN4A: Sodium channel protein type 4 subunit alpha

  Its rapid sodium current initiates and propagates skeletal-muscle action potentials. Gain- and loss-of-function variants cause disorders of muscle excitability including sodium-channel myotonia, paramyotonia congenita, periodic paralysis, and some congenital myopathies.

  6 disease-causing and 1 uncertain variants in SCN4A are linked to Skeletal muscle channelopathy.

• CACNA1S: Voltage-dependent L-type calcium channel subunit alpha-1S

  Its voltage sensing in skeletal-muscle transverse tubules mechanically activates RYR1 and couples membrane depolarization to sarcoplasmic-reticulum calcium release. Pathogenic variants can cause hypokalemic periodic paralysis, malignant-hyperthermia susceptibility, and congenital myopathy.

  1 disease-causing and 0 uncertain variants in CACNA1S are linked to Skeletal muscle channelopathy.

Weakly linked (only a few uncertain records): KCNJ2.

Where Skeletal muscle channelopathy variants cluster

• SCN4A III (positions 1013–1326): 3 of 6 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in Skeletal muscle channelopathy

Which prediction tools work for Skeletal muscle channelopathy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 92 out of 100
• SIFT: 88 out of 100
• phyloP: 86 out of 100

Same protein, different disease

• Congenital myotonia, autosomal dominant form is also caused by CLCN1 variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (92 disease-causing).
• Congenital myotonia, autosomal recessive form is also caused by CLCN1 variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (90 disease-causing).
• Hyperkalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (62 disease-causing).
• Paramyotonia congenita of Von Eulenburg is also caused by SCN4A variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (15 disease-causing).
• Potassium-aggravated myotonia is also caused by SCN4A variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (14 disease-causing).
• Hypokalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (11 disease-causing).
• Congenital myopathy 22A, classic is also caused by SCN4A variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (8 disease-causing).
• Hypokalemic periodic paralysis is also caused by CACNA1S variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (14 disease-causing).
• Myopathy is also caused by CACNA1S variants; they fall mostly in different places as the Skeletal muscle channelopathy variants (3 disease-causing).

Diseases related to Skeletal muscle channelopathy

• Hypokalemic periodic paralysis, also linked to CACNA1S, CLCN1 and SCN4A
• Hyperkalemic periodic paralysis, also linked to CLCN1 and SCN4A
• Epilepsy, also linked to CACNA1S and SCN4A
• Amyotrophic lateral sclerosis, also linked to SCN4A
• Congenital myotonia, autosomal dominant form, also linked to CLCN1
• Congenital myotonia, autosomal recessive form, also linked to CLCN1
• Cardiac arrhythmia, also linked to SCN4A
• Sotos syndrome, also linked to SCN4A
• Congenital myasthenic syndrome 17, also linked to SCN4A
• Paramyotonia congenita of Von Eulenburg, also linked to SCN4A
• Potassium-aggravated myotonia, also linked to SCN4A
• Diabetes mellitus, also linked to CACNA1S

Frequently asked questions

Which genes are linked to Skeletal muscle channelopathy?

In CATVariant, Skeletal muscle channelopathy is linked to 3 analyzed proteins: CLCN1 (Chloride channel protein 1), SCN4A (Sodium channel protein type 4 subunit alpha) and CACNA1S (Voltage-dependent L-type calcium channel subunit alpha-1S).

How many genetic variants are linked to Skeletal muscle channelopathy?

23 variants: 18 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 5 are of uncertain significance or have conflicting reports.

Which uncertain variants in Skeletal muscle channelopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Skeletal muscle channelopathy?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 15 disease-causing and 101 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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