Febrile seizures, familial, 3a: genes and variants

Genes linked to Febrile seizures, familial, 3a

• GABRG2: Gamma-aminobutyric acid receptor subunit gamma-2

  The gene product supplies the gamma-2 subunit of synaptic GABA-A receptors, which are pentameric chloride channels activated by the inhibitory neurotransmitter GABA. The subunit helps receptor assembly and localization at neuronal membranes, and GABRG2 variants are associated with several epilepsy syndromes.

  31 disease-causing and 193 uncertain variants in GABRG2 are linked to Febrile seizures, familial, 3a.

• 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.

  0 disease-causing and 0 uncertain variants in SCN1A are linked to Febrile seizures, familial, 3a.

Weakly linked (only a few uncertain records): SCN9A.

Where Febrile seizures, familial, 3a variants cluster

• GABRG2 Transmembrane (positions 303–322): 7 of 31 disease-causing changes, 5.4× more than its size predicts.
• GABRG2 Extracellular (positions 323–334): 5 of 31 disease-causing changes, 6.4× more than its size predicts.

Known disease-causing variants in Febrile seizures, familial, 3a

Uncertain variants in Febrile seizures, familial, 3a that look disease-causing

Which prediction tools work for Febrile seizures, familial, 3a

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

• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 93 out of 100
• EVE: 91 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 81 out of 100
• SIFT: 81 out of 100
• CATVariant: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 70 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 59 out of 100

Diseases related to Febrile seizures, familial, 3a

• Generalized epilepsy with febrile seizures plus, also linked to GABRG2 and SCN1A
• Epilepsy, also linked to GABRG2 and SCN1A
• Genetic developmental and epileptic encephalopathy, also linked to GABRG2 and SCN1A
• Lennox-Gastaut syndrome, also linked to GABRG2 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
• Cardiac arrhythmia, also linked to SCN1A
• EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2, also linked to GABRG2
• Migraine, familial hemiplegic, 1, also linked to SCN1A
• Self-limited epilepsy with centrotemporal spikes, also linked to GABRG2
• Familial sleep-related hypermotor epilepsy, also linked to GABRG2

Frequently asked questions

Which genes are linked to Febrile seizures, familial, 3a?

In CATVariant, Febrile seizures, familial, 3a is linked to 2 analyzed proteins: GABRG2 (Gamma-aminobutyric acid receptor subunit gamma-2) and SCN1A (Sodium channel protein type 1 subunit alpha).

How many genetic variants are linked to Febrile seizures, familial, 3a?

233 variants: 31 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 194 are of uncertain significance or have conflicting reports.

Which uncertain variants in Febrile seizures, familial, 3a look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GABRG2 P83T and GABRG2 A300D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Febrile seizures, familial, 3a?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 20 disease-causing and 22 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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