Epilepsy, idiopathic generalized, susceptibility to, 13: genes and variants

Genes linked to Epilepsy, idiopathic generalized, susceptibility to, 13

• GABRA1: Gamma-aminobutyric acid receptor subunit alpha-1

  The gene product supplies the alpha-1 subunit of a pentameric GABA-A receptor, a ligand-gated chloride channel in the brain. GABA binding allows chloride influx that dampens neuronal activity, making this receptor important for inhibition and seizure biology.

  24 disease-causing and 167 uncertain variants in GABRA1 are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

• CASR: Extracellular calcium-sensing receptor

  It senses extracellular calcium in the parathyroid gland and kidney and adjusts parathyroid-hormone secretion and renal calcium handling accordingly. Loss-of-function variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, whereas activating variants cause autosomal dominant hypocalcemia.

  8 disease-causing and 38 uncertain variants in CASR are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

• SLC2A1: Solute carrier family 2, facilitated glucose transporter member 1

  It provides basal glucose uptake in many tissues and is the principal route for glucose entry across the blood-brain barrier. Haploinsufficiency causes GLUT1 deficiency syndrome with epilepsy, developmental impairment, and movement disorders from inadequate brain glucose delivery.

  4 disease-causing and 41 uncertain variants in SLC2A1 are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

• ZFHX3: Zinc finger homeobox protein 3

  1 disease-causing and 0 uncertain variants in ZFHX3 are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

• HCN4: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

  Its hyperpolarization-activated current contributes substantially to spontaneous diastolic depolarization in sinoatrial-node pacemaker cells. Pathogenic variants can cause sinus bradycardia, conduction abnormalities, and in some families left-ventricular noncompaction.

  0 disease-causing and 48 uncertain variants in HCN4 are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

• KCNMA1: Calcium-activated potassium channel subunit alpha-1

  Its large-conductance potassium current couples membrane voltage and intracellular calcium to rapid repolarization in neurons, smooth muscle, and other excitable cells. Gain- and loss-of-function variants can cause paroxysmal dyskinesia, epilepsy, developmental impairment, and movement disorders.

  0 disease-causing and 5 uncertain variants in KCNMA1 are linked to Epilepsy, idiopathic generalized, susceptibility to, 13.

Where Epilepsy, idiopathic generalized, susceptibility to, 13 variants cluster

• GABRA1 Transmembrane (positions 280–301): 5 of 24 disease-causing changes, 4.3× more than its size predicts.
• CASR Ligand-binding 1 (LB1) (positions 22–188): 4 of 8 disease-causing changes, 3.2× more than its size predicts.
• CASR Ligand-binding 2 (LB2) (positions 189–324): 3 of 8 disease-causing changes, 3.0× more than its size predicts.

Known disease-causing variants in Epilepsy, idiopathic generalized, susceptibility to, 13

Uncertain variants in Epilepsy, idiopathic generalized, susceptibility to, 13 that look disease-causing

Which prediction tools work for Epilepsy, idiopathic generalized, susceptibility to, 13

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

• CATVariant: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 87 out of 100
• REVEL: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 79 out of 100
• AlphaMissense: 77 out of 100
• SIFT: 72 out of 100
• MetaLR: 71 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Familial hypocalciuric hypercalcemia is also caused by CASR variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (81 disease-causing).
• Autosomal dominant hypocalcemia is also caused by CASR variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (69 disease-causing).
• Nephrolithiasis/nephrocalcinosis is also caused by CASR variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (14 disease-causing).
• Neonatal severe primary hyperparathyroidism is also caused by CASR variants; they fall partly in the same places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (11 disease-causing).
• Familial hyperparathyroidism or Hypocalciuric hypercalcaemia is also caused by CASR variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (5 disease-causing).
• GLUT1 deficiency syndrome is also caused by SLC2A1 variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (53 disease-causing).
• Encephalopathy due to GLUT1 deficiency is also caused by SLC2A1 variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (32 disease-causing).
• Childhood onset GLUT1 deficiency syndrome 2 is also caused by SLC2A1 variants; they fall mostly in different places as the Epilepsy, idiopathic generalized, susceptibility to, 13 variants (18 disease-causing).

Diseases related to Epilepsy, idiopathic generalized, susceptibility to, 13

• Idiopathic generalized epilepsy, also linked to CASR, GABRA1, KCNMA1 and SLC2A1
• Cardiac arrhythmia, also linked to HCN4 and ZFHX3
• Hypertrophic cardiomyopathy, also linked to CASR
• Familial hypocalciuric hypercalcemia, also linked to CASR
• EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2, also linked to GABRA1
• Autosomal dominant hypocalcemia, also linked to CASR
• GLUT1 deficiency syndrome, also linked to SLC2A1
• Type 2 diabetes mellitus, also linked to ZFHX3
• Brugada syndrome, also linked to HCN4
• Encephalopathy due to GLUT1 deficiency, also linked to SLC2A1
• Childhood onset GLUT1 deficiency syndrome 2, also linked to SLC2A1
• Epilepsy, also linked to GABRA1

Frequently asked questions

Which genes are linked to Epilepsy, idiopathic generalized, susceptibility to, 13?

In CATVariant, Epilepsy, idiopathic generalized, susceptibility to, 13 is linked to 6 analyzed proteins: GABRA1 (Gamma-aminobutyric acid receptor subunit alpha-1), CASR (Extracellular calcium-sensing receptor), SLC2A1 (Solute carrier family 2, facilitated glucose transporter member 1), ZFHX3 (Zinc finger homeobox protein 3), HCN4 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4) and KCNMA1 (Calcium-activated potassium channel subunit alpha-1).

How many genetic variants are linked to Epilepsy, idiopathic generalized, susceptibility to, 13?

354 variants: 37 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 299 are of uncertain significance or have conflicting reports.

Which uncertain variants in Epilepsy, idiopathic generalized, susceptibility to, 13 look disease-causing?

4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GABRA1 R214S, GABRA1 N275S, GABRA1 Y187F and GABRA1 E277D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Epilepsy, idiopathic generalized, susceptibility to, 13?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 11 disease-causing and 110 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center