Intellectual disability
Gene: AGO1 Amber List (moderate evidence)Comment on list classification: Changed rating of gene from Red to Amber based on current information in the literature and external expert review. There is not enough evidence to support gene-disease association rating of this gene to Green.Created: 20 Feb 2019, 5:13 p.m.
Comment on phenotypes: Added phenotypes suggested from expert review that indicate relevance to inclusion on the ID panelCreated: 20 Feb 2019, 5:11 p.m.
Comment on publications: Added publications suggested from external expert review to support upgrading of the gene. Also added PMID: 29726122 (2018) that reports a novel 2.3 Mb, de novo, 1p34.3p34.2 deletion in a patient with who has a history of global developmental delay, mild intellectual disability, delayed bone age, bilateral vesicoureteral reflux, vocal cord paralysis, right aberrant subclavian artery, kyphoscoliosis, bilateral metatarsus adductus, and valgus knee deformity. This adds to the evolving genetic literature that haploinsufficiency of this region and genes other than AGO1, AGO3, GRIK3, SLC2A1, and RIMS3 may lead to the neurocognitive delaysCreated: 20 Feb 2019, 5:10 p.m.
AGO1 previous HGNC gene symbol was EIF2C1.Created: 20 Feb 2019, 4:59 p.m.
Comment on mode of inheritance: changed MOI- agreed with external reviewer that x linked is not appropriate for this gene and was an error.Created: 20 Feb 2019, 4:52 p.m.
Green List (high evidence)
PMID: 30213762 reports on an individual with a de novo missense variant in AGO1 [(NM_012199.2):c.595G>A p.(Gly199Ser)]. Hypotonia, intellectual disability, seizures and dysmorphic features were part of the phenotype. The same variant had previously been reported in a study by Hamdan et al. (2014) which has been cited among others by the authors.
Other de novo variants in AGO1 (EIF2C1) reported in the context of larger ID/ASD cohorts - most of these articles cited in the aforementioned case report.
PMID: 22495306 (Sanders et al, 2012) - p.(Thr355Ile) - ASD
PMID: 23020937 (Rauch et al, 2012) - p.(Leu190Pro) - Intellectual disability
PMID: 25363768 (Iossifov et al, 2014) - p.(Thr355Ile) - ASD
PMID: 25356899 (Hamdan et al, 2014) - p.(Gly199Ser) - Intellectual disability
PMID: 27620904 (Martinez et al, 2017) - p.(Gly195Lys) - Intellectual disability
PMID: 29346770 (Takata et al, 2018) - p.Gly199Val - ASD (Same residue as in 30213762 and 25356899)
In Decipher, 2 individuals from the DDD study with de novo missense SNVs (at least one of whom published in PMID: 28135719 - https://decipher.sanger.ac.uk/search?q=gene%3AAGO1#research-variants/results ).
The authors in 30213762 cite a previous publication with 1p34.3 microdeletions in individuals with intellectual disability, although the minimal region of overlap (289 kb in size) encompassed also AGO3 and other genes apart from AGO1.
This gene has been included either as AGO1 or as EIF2C1 in ID/ASD gene panels from different diagnostic labs.
As a result this gene can be considered for upgrade to amber or green.
NB. The gene is located in 1p34.3 and as a result the X-Linked inheritance mode registered in this panel does not apply (most probably due to a typo error in the supplement of PMID 26350204 where EIF2C1 is listed as an X-Linked gene).Created: 12 Oct 2018, 11:58 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Autism
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Red List (low evidence)
Candidate gene variant found in one ID proband. No association reported in OMIM nor G2PCreated: 31 Oct 2017, 9:57 a.m.
Mode of inheritance
Unknown
Publications
Red List (low evidence)
Gene: ago1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: AGO1 were changed from to Generalized hypotonia; Global developmental delay; Intellectual disability; Autism
Publications for gene: AGO1 were set to 26350204
Mode of inheritance for gene: AGO1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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.
Model of inheritance for gene AGO1 was set to Unknown Publications for gene AGO1 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
AGO1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
AGO1 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.