Intellectual disabilityGene: GABRA5 Green List (high evidence)
Comment on list classification: Upgraded from Amber to Green following advice from Genomics England clinical team. The case reported in PMID:29961870 (Butler et al 2018) had delayed milestones and is reported to be non-verbal, which is a relevant phenotype for this panel. Overall 3 unrelated cases from 2 papers.
Created: 30 Sep 2019, 1:14 p.m. | Last Modified: 30 Sep 2019, 1:14 p.m.
Panel Version: 2.1052
Comment on list classification: Updated rating from Red to Amber following external review by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM. There are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy and ID. However in Butler et al., development slowed at the time of seizure onset. Therefore rating Amber awaiting further clinical input.
Created: 20 Sep 2019, 1:06 p.m. | Last Modified: 20 Sep 2019, 1:06 p.m.
Panel Version: 2.1029
Summary of recent evidence (refer to Konstantinos Varvagiannis' review for further details):
PMID:29961870, Butler et al. 2018 report a 2 year old boy (patient 1) with EIEE and a p.V294L variant in GABRA5. Cognitive and motor development slowed at the time of seizure onset. The patient developed secondary microcephaly. A de novo variant in MIA2 was also detected but was considered unlikely to contribute to the patients phenotypes due to allele frequency in the gnomAD database.
PMID:31056671, Hernandez et al. 2019 screened a cohort of patients with epilepsy and ID and report 2 individuals with GABRA5 missense variants (V294F and S413F). Both had severe ID and delayed motor development.
Created: 20 Sep 2019, 1:02 p.m. | Last Modified: 20 Sep 2019, 1:02 p.m.
Panel Version: 2.1025
Green List (high evidence)
Heterozygous pathogenic GABRA5 variants cause Epileptic encephalopathy, early infantile, 79 (MIM 618559) [entry recently updated in OMIM].
At least 3 relevant individuals with this diagnosis have been reported to date:
- Butler et al. (2018 - PMID: 29961870) described a 2 y.o. boy with early infantile epileptic encephalopathy (seizure onset at the age of 4m). The boy was found to harbor a de novo missense variant (NM_000810.3:c.880G>C - p.Val294Leu) identified following trio-WGS and confirmed by Sanger sequencing. Studies in HEK293 cells demonstrated expression at the surface and incorporation of the mutant subunit in the channel. The α5(V294L)β2γ2s receptors were 10 times more sensitive to GABA compared to wt, but were more likely to desensitize leading to reduced maximum GABA-evoked currents.
- Hernandez et al. (2019 - PMID: 31056671) reported on 2 unrelated individuals with early-onset epileptic encephalopathy due to de novo GABRA5 variants identified by targeted NGS sequencing (480 epilepsy-related genes):
A 3y 10m male with seizure onset at the age of 4m, severe motor delay and ID, frontotemporal atrophy and thin CC upon MRI imaging was found to harbor a de novo missense variant (NM_000810.3:c.880G>T / p.Val294Phe).
A further unrelated subject (a 7 y.o. male) with seizure onset at the age of 3 months, severe DD and ID and cortical atrophy / thin CC upon MRI imaging was heterozygous for another missense variant which had occurred as a de novo event (NM_000810.3:c.1238C>T - p.Ser413Phe).
Functional studies: Expression of HA-tagged α5(V294F) subunits at dendritic GABAergic synapses of rat hippocampal neurons was decreased compared to wt, in contrast with the expression of α5(S413F) subunits which was similar to wt. As the α5(V294F) appeared accumulated in the soma of the neurons, the authors performed additional studies – using HEK293T cells – to show that while the α5(S413F) spread outside the ER, α5(V294F) subunits localized to the ER. This was suggestive of a trafficking defect/ER retention. Co-expression of wt or mutant HA-tagged subunits, with β3 and γ2 subunits in HEK293T cells was carried out to assess assembly and trafficking to cell membranes. Reduced surface levels as well as total (whole cell lysate) levels were shown for α5(V294F). Surface levels and total levels of the α5(S413F) were not changed compared to wt. Surface levels of the β3 subunit were however lower in the case of α5(S413F), a finding which could be suggestive of a dominant negative effect. Both GABRA5 mutations resulted in decreased GABA-evoked current amplitudes in both neuronal and non-neuronal (HEK293T) cells.
The corresponding phenotype in OMIM is Epileptic encephalopathy, early infantile, 79 (618559).
GABRA5 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
As a result, GABRA5 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, 3 unrelated individuals, 3 variants, supporting functional studies for all variants) or amber.
Created: 8 Sep 2019, 1:34 p.m. | Last Modified: 8 Sep 2019, 1:34 p.m.
Panel Version: 2.1022
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Epileptic encephalopathy, early infantile, 79 (MIM 618559)
Variants in this GENE are reported as part of current diagnostic practice
Gene: gabra5 has been classified as Green List (High Evidence).
Gene: gabra5 has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: GABRA5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: GABRA5 were changed from to Epileptic encephalopathy, early infantile, 79, 618559; developmental delay
Publications for gene: GABRA5 were set to
gene: GABRA5 was added gene: GABRA5 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: GABRA5 was set to
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.