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Intellectual disability

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

3 reviews

Louise Daugherty (Genomics England Curator)

Comment on phenotypes: added OMIM MIM id
Created: 19 Aug 2019, 9:37 a.m. | Last Modified: 19 Aug 2019, 9:37 a.m.
Panel Version: 2.1012
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: 2.930
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: 2.929
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: 2.928

Catherine Snow (Genomics England)

Comment from clinical team on CACNA1B, "there are sufficient cases, an appropriate phenotype and support for LOF in this gene which is a good biological candidate.
The queries raised are valid though. My thoughts are:
Proband 2 (and his brother) did not have paternal DNA for testing, however the presence of the second variant has been excluded in the mother, meaning it is likely to be inherited from Dad and therefore in trans
Proband 3 was adopted. The SNP array shows areas of homozygosity suggesting parental relatedness and she has an apparently homozygous variant. Yes, parental studies would be useful but in the context of the other cases and a LOF mechanism in a gene intolerant to LOF I would accept it
The paper outlines that a number of cases have developmental concerns or regression (Table 1) prior to the onset of seizures, therefore I would include in an ID cohort
If a gene only ever causes seizures first and developmental problems follow as a result of this, I would not tend to include in ID."
Created: 9 Jul 2019, 9:45 a.m. | Last Modified: 9 Jul 2019, 9:45 a.m.
Panel Version: 0.199
Comment on list classification: Ellen Mcdonagh reviewed and commented that "reservation on the amount of evidence is for proband 2, the father's DNA was not available, and for proband 3 both parent's DNA was not available. Definitely make it Amber, but I would want a second opinion (from the Clinical Team) on whether they would be happy to make it Green... I think this should be added to the epilepsy panel but, unsure whether it should be Green on the ID panel, as the paper states "With the onset of seizures, there was concurrent regression of previously acquired skills, and the individual developed severe intellectual disability (ID), postnatal microcephaly, a hyperkinetic movement..." therefore the seizures may have caused the developmental delay
Created: 19 Jun 2019, 4:12 p.m.
Comment on list classification: Expert review by Konstantinos Varvagiannis on CACNA1B. Gorman et al. (PMID:30982612) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants.

In OMIM, monoallelic CACNA1B pathogenic variants 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). This finding has not been replicated in subsequent studies (PMID:26157024). CACNA1B is not in G2P.

There are sufficient cases of ID/DD (>3 from PMID:30982612), thereby warranting a Green rating.
Created: 15 May 2019, 3:17 p.m.

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 pathogenic variants 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, 8:54 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
  • Expert Review
  • Expert Review Green
  • Expert Review
Phenotypes
  • Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497
  • Progressive Epilepsy-Dyskinesia
  • Seizures
  • Abnormality of movement
  • Intellectual disability
  • Developmental regression
  • Global developmental delay
OMIM
601012
Clinvar variants
Variants in CACNA1B
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

19 Aug 2019, Gel status: 3

Set Phenotypes

Louise Daugherty (Genomics England Curator)

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

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Set publications

Catherine Snow (Genomics England)

Source Expert Review was added to CACNA1B. Added phenotypes Global developmental delay; Seizures; Intellectual disability; Abnormality of movement; Developmental regression for gene: CACNA1B Publications for gene CACNA1B were changed from 30982612; 25296916 to 26157024; 30982612

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 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 Intellectual disability. 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