Intellectual disability - microarray and sequencing
Gene: KCNN3 Green List (high evidence)The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Green List (high evidence)
Gripp et al 2021 reported three additional patients with gain-of-function KCNN3 variants (two de novo and one not known- father not tested, not maternal): NM_002249.6 c.1663G > T p.(Val555Phe), c.1616_1618del p.(Val539del) and c.859G > T p.(Ala287Ser). The authors noted the overlap in the phenotype due to KCNN3, KCNH1 and KCNK4 variants with moderate developmental delay or mild-to-moderate intellectual disability, coarse facial features, gingival enlargement, distal digital hypoplasia and hypertrichosis and proposed to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance.Created: 20 Feb 2021, 5:48 p.m. | Last Modified: 20 Feb 2021, 5:48 p.m.
Panel Version: 3.963
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental delay; ID; hypotonia; gingival enlargement; hypertrichosis; nail anomalies
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
Green List (high evidence)
Now at least 6 unrelated individuals with different gain-of-function KCNN3 variants (PMIDs: 31155282 and 33594261). Phenotypes include mild-to-moderate DD and/or ID.Created: 1 Mar 2021, 11:10 a.m. | Last Modified: 1 Mar 2021, 11:10 a.m.
Panel Version: 3.966
Comment on mode of pathogenicity: Gain-of-function variants identified in all patients reported to date.Created: 24 Jul 2020, 12:17 p.m. | Last Modified: 26 Feb 2021, 12:31 p.m.
Panel Version: 3.966
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - three unrelated cases with relevant phenotype, although future re-evaluation of the two younger patients may be useful.Created: 24 Jul 2020, 12:12 p.m. | Last Modified: 24 Jul 2020, 12:12 p.m.
Panel Version: 3.192
Associated with phenotype in OMIM, and probable gene-disease association in G2P.
Bauer et al. (2019) PMID: 31155282 - De novo heterozygous gain-of-function variants identified in three unrelated individuals with ZimmermannLaband syndrome. Mild-moderate ID was reported in a 46-year-old man, while developmental delay was noted for the other two patients: a 4.5-year-old (first words at 2.5 y; attends nursery) and 5.5-year-old girl (limited spoken language; attends school with a personal aide). Additional features include coarse face, gingival hyperplasia, and/or nail hypo- or aplasia.Created: 24 Jul 2020, 11:08 a.m. | Last Modified: 24 Jul 2020, 12:04 p.m.
Panel Version: 3.191
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Zimmermann-Laband syndrome 3, 618658
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments
Green List (high evidence)
Three unrelated individuals reported.
Sources: Expert listCreated: 8 Feb 2020, 9:32 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Zimmermann-Laband syndrome 3; OMIM# 618658
Publications
Variants in this GENE are reported as part of current diagnostic practice
Tag for-review was removed from gene: KCNN3.
Source Expert Review Green was added to KCNN3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: KCNN3 were set to 31155282
Phenotypes for gene: KCNN3 were changed from Zimmermann-Laband syndrome 3; OMIM# 618658 to Zimmermann-Laband syndrome 3, OMIM:618658
Mode of pathogenicity for gene: KCNN3 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Gene: kcnn3 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: KCNN3.
gene: KCNN3 was added gene: KCNN3 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNN3 were set to 31155282 Phenotypes for gene: KCNN3 were set to Zimmermann-Laband syndrome 3; OMIM# 618658 Review for gene: KCNN3 was set to GREEN gene: KCNN3 was marked as current diagnostic
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.