Migraine, familial hemiplegic, 1: genes and variants

Genes linked to Migraine, familial hemiplegic, 1

• CACNA1A: Voltage-dependent P/Q-type calcium channel subunit alpha-1A

  Its P/Q-type calcium current is a major trigger for neurotransmitter release at central synapses and is especially important in cerebellar circuits. Pathogenic variants cause a spectrum including familial hemiplegic migraine, episodic ataxia, spinocerebellar ataxia type 6, epilepsy, and developmental disorders.

  26 disease-causing and 39 uncertain variants in CACNA1A are linked to Migraine, familial hemiplegic, 1.

• SCN1A: Sodium channel protein type 1 subunit alpha

  Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine.

  20 disease-causing and 36 uncertain variants in SCN1A are linked to Migraine, familial hemiplegic, 1.

• ATP1A2: Sodium/potassium-transporting ATPase subunit alpha-2

  It restores sodium and potassium gradients after activity in astrocytes and other excitable tissues and thereby supports neuronal ion homeostasis. Pathogenic variants are a major cause of familial hemiplegic migraine type 2 and can produce severe episodic neurologic disease.

  19 disease-causing and 34 uncertain variants in ATP1A2 are linked to Migraine, familial hemiplegic, 1.

Weakly linked (only a few uncertain records): WDR45.

Where Migraine, familial hemiplegic, 1 variants cluster

• CACNA1A S4 of repeat III (positions 1339–1357): 4 of 26 disease-causing changes, 20.3× more than its size predicts.
• CACNA1A S6 of repeat II (positions 689–713): 4 of 26 disease-causing changes, 15.4× more than its size predicts.
• SCN1A Extracellular (positions 385–397): 3 of 20 disease-causing changes, 23.2× more than its size predicts.
• CACNA1A IV (positions 1550–1813): 7 of 26 disease-causing changes, 2.6× more than its size predicts.
• SCN1A III (positions 1200–1514): 7 of 20 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Migraine, familial hemiplegic, 1

Showing 60 of 65.

Which prediction tools work for Migraine, familial hemiplegic, 1

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

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 95 out of 100
• AlphaMissense: 94 out of 100
• CADD: 93 out of 100
• SIFT: 90 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 78 out of 100

Same protein, different disease

• Episodic ataxia type 2 is also caused by CACNA1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (93 disease-causing).
• Spinocerebellar ataxia type 6 is also caused by CACNA1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (28 disease-causing).
• Early-infantile DEE is also caused by SCN1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (422 disease-causing).
• Severe myoclonic epilepsy in infancy is also caused by SCN1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (213 disease-causing).
• Generalized epilepsy with febrile seizures plus is also caused by SCN1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (76 disease-causing).
• Autosomal dominant epilepsy is also caused by SCN1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (4 disease-causing).
• Epilepsy is also caused by SCN1A variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (4 disease-causing).
• Familial hemiplegic migraine is also caused by ATP1A2 variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (33 disease-causing).
• Alternating hemiplegia of childhood is also caused by ATP1A2 variants; they fall mostly in different places as the Migraine, familial hemiplegic, 1 variants (7 disease-causing).

Diseases related to Migraine, familial hemiplegic, 1

• Epilepsy, also linked to CACNA1A and SCN1A
• Focal epilepsy, also linked to CACNA1A and SCN1A
• Early-infantile DEE, also linked to SCN1A
• Severe myoclonic epilepsy in infancy, also linked to SCN1A
• Amyotrophic lateral sclerosis, also linked to SCN1A
• Episodic ataxia type 2, also linked to CACNA1A
• Generalized epilepsy with febrile seizures plus, also linked to SCN1A
• Cardiac arrhythmia, also linked to SCN1A
• Spinocerebellar ataxia type 6, also linked to CACNA1A
• Familial hemiplegic migraine, also linked to ATP1A2
• Febrile seizures, familial, 3a, also linked to SCN1A
• Alternating hemiplegia of childhood, also linked to ATP1A2

Frequently asked questions

Which genes are linked to Migraine, familial hemiplegic, 1?

In CATVariant, Migraine, familial hemiplegic, 1 is linked to 3 analyzed proteins: CACNA1A (Voltage-dependent P/Q-type calcium channel subunit alpha-1A), SCN1A (Sodium channel protein type 1 subunit alpha) and ATP1A2 (Sodium/potassium-transporting ATPase subunit alpha-2).

How many genetic variants are linked to Migraine, familial hemiplegic, 1?

205 variants: 65 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 110 are of uncertain significance or have conflicting reports.

Which uncertain variants in Migraine, familial hemiplegic, 1 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 Migraine, familial hemiplegic, 1?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 36 disease-causing and 23 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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