Intellectual disabilityGene: VPS11 Amber List (moderate evidence)
There is also functional data to support this gene-disease association. This gene is also rated Green on the Genetic epilepsy syndromes (Version 2.339)
Created: 6 May 2021, 3:42 p.m. | Last Modified: 6 May 2021, 3:42 p.m.
Panel Version: 3.1066
Comment on list classification: Gene identified by an expert review by Konstantinos Varvagiannis. Although Konstantinos Varvagiannis suggests that this should be green. PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families, all with the same variant, therefore reported as a founder effect. A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents of a Turkish origin (PMID: 27473128). VPS11 is in OMIM and ID phenotype is relevant.
However as only two unique variants have been identified so far, classifying VPS11 as Amber and adding to the watch list.
Created: 28 May 2019, 9:48 a.m. | Last Modified: 25 Jun 2019, 3:05 p.m.
Panel Version: 0.194
Green List (high evidence)
Biallelic mutations in VPS11 cause Leukodystrophy, hypomyelinating, 12 (MIM 616683).
PMIDs: 27120463, 26307567, 27473128 all report on this disorder.
The phenotype consists of global DD, ID, (variable) acquired microcephaly with hypomyelination upon brain MRI. Seizures appear to be a feature in several individuals.
Almost all individuals appear to be of Ashkenazi Jewish descent, homozygous for a founder mutation (NM_021729.5:c.2536T>G or p.Cys846Gly). PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families.
A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents.
Pathogenicity is supported by extensive functional studies in all relevant articles.
VPS11 is not associated with any phenotype in G2P.
The gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
As a result, this gene can be considered for inclusion in this panel as green.
[Please consider inclusion in the lysosomal disorders panel as well as in the undiagnosed metabolic disorders panel].
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 14 Dec 2018, 4:02 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy, hypomyelinating, 12 (MIM 616683)
Variants in this GENE are reported as part of current diagnostic practice
Tag watchlist was removed from gene: VPS11. Tag Q2_21_rating tag was added to gene: VPS11.
Tag watchlist tag was added to gene: VPS11.
Source Expert Review was added to VPS11. Source Expert Review Amber was added to VPS11. Added phenotypes Leukodystrophy, hypomyelinating, 12, 616683 for gene: VPS11 Publications for gene VPS11 were changed from 27120463; 26307567; 27473128 to 27473128; 26307567; 27120463 Rating Changed from No List (delete) to Amber List (moderate evidence)
gene: VPS11 was added gene: VPS11 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: VPS11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS11 were set to 27120463; 26307567; 27473128 Phenotypes for gene: VPS11 were set to Leukodystrophy, hypomyelinating, 12 (MIM 616683) Penetrance for gene: VPS11 were set to Complete Review for gene: VPS11 was set to GREEN gene: VPS11 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).
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).
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.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
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.