Intellectual disability - microarray and sequencing
Gene: GABBR2 Green List (high evidence)Added missense tag: only missense variants (A707T and A567T) reported so far in the literature.Created: 29 Aug 2019, 1:19 p.m. | Last Modified: 29 Aug 2019, 1:19 p.m.
Panel Version: 2.1021
Comment on list classification: Updated gene from Amber to Green: As noted by Konstantinos Varvagiannis, an additional 2018 study has been published associating a new GABBR2 variant (A707T) with a RETT-like phenotype including intellectual impairment (PMID:29369404). This adds to the previous papers documenting the recurring p.Ala567Thr variant in RETT-like patients from Portugal (PMID:26740508) and Korea (PMID:28856709). Plus OMIM has been updated since the Dec 2017 curation to include neurodevelopmental disorder MIM:617904. Thirdly, email correspondence from J. Evans notes a patient with a relevant phenotype and a previously-published pathogenic variant in GABBR2. Therefore sufficient unrelated cases to support a Green rating.Created: 29 Aug 2019, 1:18 p.m. | Last Modified: 29 Aug 2019, 1:18 p.m.
Panel Version: 2.1021
PMID:29369404: Vuillaume et al., 2018 report de novo heterozygous variant A707T in a 12 year old girl with profound ID and no history of seizures. Functional studies showed the resulting protein had impaired signaling.Created: 29 Aug 2019, 1:12 p.m. | Last Modified: 29 Aug 2019, 1:12 p.m.
Panel Version: 2.1020
I don't know
PMID 29369404 describes a 12 year-old girl with a de novo - previously unreported - missense variant and a Rett-like phenotype (intellectual disability, stereotypies, sleeping and breathing disorder but no seizures).Created: 12 Aug 2018, 10:41 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
EPILEPTIC ENCEPHALOPATHY; Rett syndrome
Publications
I don't know
This is a Possible DD gene for Epileptic encephalopathy. No relevant diseases in OMIM. PMID: 29100083 - 1 patient with a de novo missense variant in this gene in the CENet Cohort is reported. He presented with severe global developmental delay and seizures, with profound intellectual deficiency. PMID: 28061363 - 2 individuals reported with de novo variants in this gene in an analysis by EuroEPINOMICS and Epi4K/EPGP of a large cohort of trios with epileptic encephalopathies, infantile spasms or Lennox Gastaut syndrome. Knock out mice experience spontaneous seizures and severe memory impairment. PMID: 26740508 - de novo missense variant in this gene and a homozygous variant in EIF4G1 were identified in this gene in a female patient with Rett syndrome including severe ID (without seizures). DDD project identified a de novo missense variants in 2 males and a female which were validated (PMID:28135719). PMID: 28856709 - the same de novo variant was identified in four unrelated patients with a Rett-like phenotype.Created: 13 Dec 2017, 9:46 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
EPILEPTIC ENCEPHALOPATHY; Rett syndrome
Publications
Red List (low evidence)
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
EPILEPTIC ENCEPHALOPATHY
Publications
Red List (low evidence)
Tag missense tag was added to gene: GABBR2.
Gene: gabbr2 has been classified as Green List (High Evidence).
Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome to EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Neurodevelopmental disorder with poor language and loss of hand skills, 617903
Publications for gene: GABBR2 were set to 29100083; 28061363; 28135719; 28856709
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
This gene has been classified as Amber List (Moderate Evidence).
Model of inheritance for gene GABBR2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene GABBR2 was set to ['29100083', '28061363', '28135719', '28856709']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
GABBR2 was added to Intellectual disabilitypanel. Sources: Expert Review Red
GABBR2 was created by ellenmcdonagh
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).
OR
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).
OR
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.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
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.