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Genetic epilepsy syndromes

Gene: CACNA1B

Green List (high evidence)

CACNA1B (calcium voltage-gated channel subunit alpha1 B)
EnsemblGeneIds (GRCh38): ENSG00000148408
EnsemblGeneIds (GRCh37): ENSG00000148408
OMIM: 601012, Gene2Phenotype
CACNA1B is in 4 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:17 a.m. | Last Modified: 9 Sep 2019, 10:17 a.m.
Panel Version: 1.314
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AR NEDNEH. Gormn et al, 2019 (30982612) - 6 patients from 3 unrelated families with a similar neurodev disorder. A consang family from Pakistan contained 3 aff sibs, a non-consang European family with 2 aff sibs, and a single patient of Bulgarian descent - adopted with unknow family history. All patiens died between 3 and 17 years of age.mainly from respiatory failure except the Bulgarian girl who was still alive aged 6. All had onset of refractory, focal, generalised or myoclonic seizures. Biallelic mutations identified in all 3 families - all wwre predicted to cause LOF through nonsense medicated decay and/or premature termination of translation.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Louise Daugherty (Genomics England Curator)

Comment on phenotypes: added OMIM MIM id
Created: 19 Aug 2019, 9:36 a.m. | Last Modified: 19 Aug 2019, 9:36 a.m.
Panel Version: 1.253
Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Created: 1 Jul 2019, 3:13 p.m. | Last Modified: 1 Jul 2019, 3:13 p.m.
Panel Version: 1.96
Comment on phenotypes: added Progressive Epilepsy-Dyskinesia from PMID:30982612. gene-phenotype currently not listed in OMIM
Created: 1 Jul 2019, 3:12 p.m. | Last Modified: 1 Jul 2019, 3:12 p.m.
Panel Version: 1.94
Comment on publications: added publication to support gene-disease association
Created: 1 Jul 2019, 3:11 p.m. | Last Modified: 1 Jul 2019, 3:11 p.m.
Panel Version: 1.90

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Gorman et al. (2019 - doi.org/10.1016/j.ajhg.2019.03.005) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants. The phenotype corresponds to a developmental epilepic encephalopathy with hyperkinetic movement disorder (ID was a universal feature, DD and/or regression occurred prior to the onset of seizures in several individuals) .

CACNA1B encodes calcium channel, voltage-dependent N type, α-1B subunit (Ca v2.2). As commented by the authors, Ca v2.1 and v2.2 are important for SNARE-mediated release of neurotransmitters through modulation of Ca+2 levels. In addition, Ca v2.2 has been postulated to have a role in synaptic plasticity, synaptogenesis, migration of immature neurons, etc. It is thought to have a crucial role in neurotransmission in the early postnatal period (Ca v2.2 channels are subsequently replaced by Ca v2.1 in mature synapses within the thalamus, cerebellum and auditory brainstem). Knockout mice display neurodevelopmental abnormalities including impaired locomotor activity and memory impairment (all ref. cited within the article).

3 sibs, born to 1st cousin parents, harbored p.Leu1222Argfs*29 (NM_000718.4:c.3665del) in the homozygous state. One additional individual was homozygous for p.Arg383*. Compound heterozygosity for a frameshift and a splicing variant (p,Gly1192Cysfs* and c.4857+1G>C) was identified in 2 sibs from a 3rd family.

Expression/functional studies have not been performed for any of the variants reported.

In OMIM, monoallelic CACNA1B mutations are associated with ?Dystonia 23 (MIM 614860) based on the identification of a heterozygous missense (R1389H) mutation in members of a Dutch with myoclonus-dystonia syndrome (Groen et al. 2015 - PMID: 25296916).

As a result, this gene can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Created: 15 Apr 2019, 8:52 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
Phenotypes
  • Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497
  • Global developmental delay
  • Developmental regression
  • Seizures
  • Intellectual disability
  • Abnormality of movement
  • Progressive Epilepsy-Dyskinesia
OMIM
601012
Clinvar variants
Variants in CACNA1B
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to CACNA1B.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to CACNA1B.

19 Aug 2019, Gel status: 3

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia to Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497; Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia

1 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: cacna1b has been classified as Green List (High Evidence).

1 Jul 2019, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia

1 Jul 2019, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia

1 Jul 2019, Gel status: 0

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CACNA1B were set to

15 Apr 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: CACNA1B was added gene: CACNA1B was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CACNA1B were set to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement Penetrance for gene: CACNA1B were set to Complete Review for gene: CACNA1B was set to GREEN