Hyperkalemic periodic paralysis: genes and variants

Genes linked to Hyperkalemic periodic paralysis

• 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.

  62 disease-causing and 765 uncertain variants in SCN4A are linked to Hyperkalemic periodic paralysis.

• 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.

  1 disease-causing and 0 uncertain variants in CLCN1 are linked to Hyperkalemic periodic paralysis.

Where Hyperkalemic periodic paralysis variants cluster

• SCN4A S4 of repeat II (positions 665–682): 7 of 62 disease-causing changes, 11.5× more than its size predicts.
• SCN4A Cytoplasmic (positions 1463–1481): 7 of 62 disease-causing changes, 10.9× more than its size predicts.
• SCN4A S4 of repeat IV (positions 1446–1462): 6 of 62 disease-causing changes, 10.4× more than its size predicts.
• SCN4A Cytoplasmic (positions 1143–1159): 5 of 62 disease-causing changes, 8.7× more than its size predicts.
• SCN4A S1 of repeat IV (positions 1355–1372): 4 of 62 disease-causing changes, 6.6× more than its size predicts.

Known disease-causing variants in Hyperkalemic periodic paralysis

Showing 60 of 63.

Uncertain variants in Hyperkalemic periodic paralysis that look disease-causing

Which prediction tools work for Hyperkalemic periodic paralysis

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

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• SIFT: 94 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 80 out of 100

Same protein, different disease

• Paramyotonia congenita of Von Eulenburg is also caused by SCN4A variants; they fall partly in the same places as the Hyperkalemic periodic paralysis variants (15 disease-causing).
• Potassium-aggravated myotonia is also caused by SCN4A variants; they fall in the same places as the Hyperkalemic periodic paralysis variants (14 disease-causing).
• Hypokalemic periodic paralysis is also caused by SCN4A variants; they fall in the same places as the Hyperkalemic periodic paralysis variants (11 disease-causing).
• Congenital myopathy 22A, classic is also caused by SCN4A variants; they fall in the same places as the Hyperkalemic periodic paralysis variants (8 disease-causing).
• Congenital myasthenic syndrome 17 is also caused by SCN4A variants; they fall partly in the same places as the Hyperkalemic periodic paralysis variants (7 disease-causing).
• Congenital myotonia, autosomal dominant form is also caused by CLCN1 variants; they fall mostly in different places as the Hyperkalemic periodic paralysis variants (92 disease-causing).
• Congenital myotonia, autosomal recessive form is also caused by CLCN1 variants; they fall mostly in different places as the Hyperkalemic periodic paralysis variants (90 disease-causing).
• Skeletal muscle channelopathy is also caused by CLCN1 variants; they fall mostly in different places as the Hyperkalemic periodic paralysis variants (11 disease-causing).

Diseases related to Hyperkalemic periodic paralysis

• Hypokalemic periodic paralysis, also linked to CLCN1 and SCN4A
• Skeletal muscle channelopathy, also linked to CLCN1 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
• Epilepsy, also linked to SCN4A
• Paramyotonia congenita of Von Eulenburg, also linked to SCN4A
• Potassium-aggravated myotonia, also linked to SCN4A
• Congenital myopathy 22A, classic, also linked to SCN4A

Frequently asked questions

Which genes are linked to Hyperkalemic periodic paralysis?

In CATVariant, Hyperkalemic periodic paralysis is linked to 2 analyzed proteins: SCN4A (Sodium channel protein type 4 subunit alpha) and CLCN1 (Chloride channel protein 1).

How many genetic variants are linked to Hyperkalemic periodic paralysis?

843 variants: 63 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 765 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hyperkalemic periodic paralysis look disease-causing?

9 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SCN4A A715T, SCN4A S1434Y, SCN4A R1454Q, SCN4A R1463C and SCN4A F1705L. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Hyperkalemic periodic paralysis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 28 disease-causing and 31 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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