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Genetic epilepsy syndromes

Gene: ATP1A2

Green List (high evidence)

ATP1A2 (ATPase Na+/K+ transporting subunit alpha 2)
EnsemblGeneIds (GRCh38): ENSG00000018625
EnsemblGeneIds (GRCh37): ENSG00000018625
OMIM: 182340, Gene2Phenotype
ATP1A2 is in 14 panels

9 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

Familial hemiplegic migraine not epilepsy or a seizure per se. PMID 29610157 provides a case with partial seizures. There have been reports of other cases where epilepsy was a feature reported in the literature, e.g. PMIDs 23918834, 24097848, 23838748
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Alternating hemiplegia of childhood 1, 104290 ; Migraine familial basilar, 602481 ; Migraine, familial hemiplegic, 2, 602481

Publications

Rebecca Foulger (Genomics England curator)

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Created: 15 Aug 2019, 10:04 a.m. | Last Modified: 15 Aug 2019, 10:04 a.m.
Panel Version: 1.228
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Updated rating from Amber to Green after discussion with Sarah Leigh; Sufficient cases from PMIDs:28058944, 18028407 and 12953268 of patients with familial hemiplegic migraine (FHM) also exhibiting seizures; PMID:28058944 (Prontera et al., 2018) calculate a co-occurrence of ~30%.
Created: 16 May 2019, 3:29 p.m.
PMID:28058944 (Prontera et al., 2018) performed a review of the comorbidities of familial/sporadic hemiplegic migraine with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations. For patients carrying ATP1A2 variants, 30.9% of migraine patients also had seizures 62/180 patients (the 180 patients covered 27 families).
Created: 16 May 2019, 3:02 p.m.
Vanmolkot et al., 2003 (PMID:12953268) describe novel variants in ATP1A2 in two families with FHM. The M731T variant was found in a family with pure FHM. The R689Q variant was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate; all available affected family members with FHM, benign familial infantile convulsions, or both, carried the ATP1A2 mutation.
Created: 16 May 2019, 2:59 p.m.
PMID:18028407 (Deprez et al., 2008) found ATP1A2 variants in 2/20 families (p.Gly900Arg and p.Cys702Tyr). In the two families, 6 variant carriers had the combination of epilepsy and migraine, 2 had only epilepsy, and 6 had only migraine.
Created: 16 May 2019, 2:59 p.m.
Comment on phenotypes: OMIM reports Generalized tonic-clonic seizures in 50% patients with 'Alternating hemiplegia of childhood 1' (MIM:104290) but says seizures are less common in Migraine, familial basilar/Migraine, familial hemiplegic, 2 (OMIM:602481).
Created: 16 May 2019, 2:59 p.m.
PMID:29610157 (Ueda et al., 2018) report a 12 year old boy with a history of complex partial seizures, ADHD and fine motor difficulty. WES revealed a de novo missense variant in ATP1A2, and a maternally inherited POLG VUS. The authors hypothesize that the ATP1A2 variant contributed to the patient's phenotype.
Created: 16 May 2019, 2:58 p.m.
Comment on publications: PMID:9579893 (Terwindt et al., 1997) studied a large Dutch-Canadian family in which familial hemiplegic migraine (FHM) and a benign familial infantile epileptic syndrome concur and partially cosegregate. The genetic basis of the conditions was not finalised. Note that ATP1A2 is on chromosome 1q23.2.
Created: 16 May 2019, 2:54 p.m.

Deb Pal (King's College London)

Green List (high evidence)

Currently on Amplexa CHE-113 epilepsy diagnostic panel
Created: 12 Feb 2019, 1:50 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Familial hemiplegic migraine; Epilepsy

Publications

Variants in this GENE are reported as part of current diagnostic practice

Zornitza Stark (Australian Genomics)

Green List (high evidence)

This publication says 30% of patients with ATP1A2 mutations and hemiplegic migraine have seizures, and OMIM says 50% of alternating hemiplegia patients have seizures. I think that makes it a common rather than rare feature of these disorders.
Created: 7 Aug 2018, 9:31 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Variants in this GENE are reported as part of current diagnostic practice

Sarah Leigh (Genomics England Curator)

Comment on list classification: Associated with phenotype in OMIM, not in G2P. Seizures an uncommon feature of the phenotypes.
Created: 25 Jun 2018, 1:34 p.m.

Amy McTague (UCL Institute of Child Health)

Red List (low evidence)

Natalie Trump (NHS - Great Ormond Street Hospital)

Red List (low evidence)

Manju Kurian (UCL-Institute of Child Health)

Red List (low evidence)

Richard Scott (North Thames GMC/UCL)

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert
Phenotypes
  • Alternating hemiplegia of childhood 1, 104290
  • Migraine, familial basilar, 602481
  • Migraine, familial hemiplegic, 2, 602481
  • benign familial infantile convulsions
  • epilepsy and migraine
  • occipitotemporal epilepsy
  • infantile epileptic syndrome
OMIM
182340
Clinvar variants
Variants in ATP1A2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: atp1a2 has been classified as Green List (High Evidence).

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to ATP1A2.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to ATP1A2.

16 May 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: atp1a2 has been classified as Green List (High Evidence).

16 May 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome

16 May 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1 104290; Migraine, familial basilar 602481; Migraine, familial hemiplegic, 2 602481 to Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome

16 May 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: ATP1A2 were set to 15159495; 29610157

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Sarah Leigh: Comment on list classification

26 Sep 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: atp1a2 has been classified as Amber List (Moderate Evidence).

25 Jun 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: atp1a2 has been classified as Amber List (Moderate Evidence).

25 Jun 2018, Gel status: 1

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: ATP1A2 were set to Alternating hemiplegia of childhood 1 104290; Migraine, familial basilar 602481; Migraine, familial hemiplegic, 2 602481

25 Jun 2018, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: ATP1A2 were set to 15159495; 29610157

25 Jun 2018, Gel status: 1

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for gene: ATP1A2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

4 Apr 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

ATP1A2 was added to Genetic Epilepsy Syndromes panel. Sources: Expert,Expert Review Red

4 Apr 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

ATP1A2 was created by Sarah Leigh