Intellectual disability - microarray and sequencing
Gene: ANK3 Green List (high evidence)Green List (high evidence)
The rating of this gene has been updated to Green and the mode of inheritance updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Changing the Q2_22_MOI tag for Q3_MOI_tag so that the MOI proposed change is also included in the next GMS report.Created: 6 Oct 2022, 2:45 p.m. | Last Modified: 6 Oct 2022, 2:45 p.m.
Panel Version: 3.1737
Green List (high evidence)
Monoallelic LOF variants disrupt all 3 transcripts, biallelic LOF disrupt only the largest brain-specific isoform (PMID 28687526, 34218362).Created: 2 Sep 2022, 9:20 a.m. | Last Modified: 2 Sep 2022, 9:20 a.m.
Panel Version: 3.1701
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Intellectual disability
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
Green List (high evidence)
In the paper PMID: 34218362 four unrelated novel, and two previously published patients with heterozygos ANK3 LoF variants are reported/summarized. Additionally, three different (isoform specific) recessive LoF variants are mentioned.Created: 2 Dec 2021, 11:35 a.m. | Last Modified: 2 Dec 2021, 11:35 a.m.
Panel Version: 3.1475
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Intellectual disability
Publications
Red List (low evidence)
Green List (high evidence)
Comment on mode of inheritance: Due to the reports of heterozygous variants in PMIDs: 23390136; 28687526; 34218362, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomalCreated: 15 Sep 2022, 11:50 a.m. | Last Modified: 15 Sep 2022, 11:50 a.m.
Panel Version: 3.1716
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 15 Sep 2022, 11:48 a.m. | Last Modified: 15 Sep 2022, 11:48 a.m.
Panel Version: 3.1715
Associated with Intellectual developmental disorder, autosomal recessive 37 (OMIM:615493) in OMIM, but not associated with a phenotype in Gen2Phen. At least six ANK3 variants have now been associated with an autosomal dominant neurodevelopmental condition (PMIDs: 23390136; 28687526; 34218362). These terminating variants affect the transcripts for all of the ANK3 isoforms and are de novo (where trio evidence is available).Created: 15 Sep 2022, 11:47 a.m. | Last Modified: 15 Sep 2022, 11:47 a.m.
Panel Version: 3.1714
Associated with phenotype in OMIM, not in G2P. At least 1 variant reported in 3 Pakistani sibs, born of consanguineous parents.Created: 31 Oct 2017, 9:57 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
?Mental retardation, autosomal recessive, 37 615493
Publications
Red List (low evidence)
Tag Q3_22_rating was removed from gene: ANK3. Tag Q3_22_MOI was removed from gene: ANK3. Tag Q3_22_NHS_review was removed from gene: ANK3.
Source NHS GMS was added to ANK3. Source Expert Review Green was added to ANK3. Mode of inheritance for gene ANK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q2_22_MOI was removed from gene: ANK3. Tag Q3_22_MOI tag was added to gene: ANK3.
Tag Q2_22_MOI tag was added to gene: ANK3. Tag Q3_22_rating tag was added to gene: ANK3. Tag Q3_22_NHS_review tag was added to gene: ANK3.
Mode of inheritance for gene: ANK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Gene: ank3 has been classified as Amber List (Moderate Evidence).
Publications for gene: ANK3 were set to 23390136; 34218362
Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210
Publications for gene: ANK3 were set to 23390136
Source Victorian Clinical Genetics Services was added to ANK3.
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 ANK3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene ANK3 was set to ['23390136']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ANK3 was created by ellenmcdonagh
ANK3 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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.