Genetic Epilepsy
Gene: GLS Green List (high evidence)I don't know
PMID: 37151363 has a 2nd case report for the dominant condition. A 4yo boy with epilepsy and developmental delay and strongly increased concentrations of glutamate and decreased glutamine in the brain. Noted to NOT have cataracts. De novo for NM_014905.4: c.1382A > T; p.(His461Leu) absent from gnomad.
PMID: 35803560: report a 3rd de novo missense in this gene NM_014905(GLS):c.866A > T (p.Lys289Ile). However this patient died at seven years of age with severe, progressive spastic quadriplegia, vasculitic skin rash since infancy and a
heterogeneous white matter signal abnormality with diffuse atrophy on MRI. This paper notes that the original proband in PMID: 30239721 also had a vasculitic rash (described as dermatological abnormalities in the original paper). The original proband is also noted as having "profound axial hypotonia leading to kyphoscoliosis" and "uncontrolled motoric agitation and self-injurious behavior."
Still amber for the dominant condition, limited by ClinGen for this
CASGID syndrome MIM#618339Created: 21 Nov 2025, 4:44 p.m. | Last Modified: 21 Nov 2025, 4:44 p.m.
Panel Version: 1.3634
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
CASGID syndrome MIM#618339
Green List (high evidence)
PMID 38622440: additional individual reported with bi-allelic variants.
Note GoF variants also postulated to cause a neurodevelopmental phenotype, including seizures, though evidence is more limited, PMID 37151363. Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685Created: 8 Aug 2024, 7:33 a.m. | Last Modified: 8 Aug 2024, 7:33 a.m.
Panel Version: 1.36
Three individuals from two unrelated families reported with early neonatal refractory seizures, structural brain abnormalities and oedema; significantly increased glutamine levels.
Sources: Expert listCreated: 3 Jan 2020, 10:28 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Publications
Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Publications for gene: GLS were set to 30575854
Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: gls has been classified as Green List (High Evidence).
Gene: gls has been classified as Amber List (Moderate Evidence).
Gene: gls has been classified as Amber List (Moderate Evidence).
gene: GLS was added gene: GLS was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Expert list Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GLS were set to 30575854 Phenotypes for gene: GLS were set to Epileptic encephalopathy, early infantile, 71, MIM# 618328 Review for gene: GLS was set to AMBER
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 panelapp@genomicsengland.co.uk
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.