Intellectual disability - microarray and sequencing
Gene: VPS53 Green List (high evidence)Comment on list classification: After internal clinical review it was decided that this gene could be rated Green. Even though there is a founder effect in this population, there is further evidence for it being the gene of interest by the fact that there is more than one variant identified. There are 4 unrelated families and two variants.Created: 20 Jul 2018, 11:49 a.m.
Comment on phenotypes: added phenotypes to support gene on ID panel . All 10 patients of the four apparently unrelated non-consanguineous Jewish Moroccan families had profound mental retardation, gaining practically no developmental milestones except visual tracking and smiling.Created: 16 Jul 2018, 1:59 p.m.
Comment on list classification: New Amber gene added by external expert review, publications support gene-disease association and noted from literature and review this is a founder-effect gene. Referred to internal clinical to consider rating Green review due to presence of missense and splice site variantsCreated: 16 Jul 2018, 1:51 p.m.
added founder-effect tagCreated: 16 Jul 2018, 1:46 p.m.
It was noted by Feinstein et al. (2014) that the variants segregated with the disorder in the families. The Q695R substitution occured at a highly conserved residue in the second helix of the surface of the C terminus. Study of patient lymphocytes suggested that the splice site mutation was either subject to nonsense-mediated mRNA decay or resulted in a truncated protein. Of Jewish Moroccan controls tested, 2 of 143 carried the missense mutation and 2 of 156 carried the splice site mutation, yielding a carrier frequency of 1 in 37 for each of the mutations in this population, consistent with a founder effectCreated: 16 Jul 2018, 1:44 p.m.
Comment on publications: PMID:24577744. In 10 affected individuals from 4 nonconsanguineous families of Jewish Moroccan descent with pontocerebellar hypoplasia type 2E (PCH2E; 615851), Feinstein et al. (2014) identified two compound heterozygous mutations in the VPS53 gene. NM_001128159.2(VPS53):c.2084A>G (p.Gln695Arg) and NM_001128159.2(VPS53):c.1556+5G>ACreated: 16 Jul 2018, 1:36 p.m.
Comment on phenotypes: added omim MIMid and Orphanet phenotypeCreated: 16 Jul 2018, 1:31 p.m.
I don't know
10 individuals from 4 families reported in the literature with bi-allelic variants, but ?founder effect. Consider inclusion as Amber if not Green.Created: 22 Jun 2018, 3:05 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Pontocerebellar hypoplasia, type 2E
Publications
Variants in this GENE are reported as part of current diagnostic practice
Source Victorian Clinical Genetics Services was added to VPS53.
Gene: vps53 has been classified as Green List (High Evidence).
Phenotypes for gene: VPS53 were set to Pontocerebellar hypoplasia, type 2E, 615851; Progressive cerebello-cerebral atrophy; intellectual disability; developmental delay
Gene: vps53 has been classified as Amber List (Moderate Evidence).
Publications for gene: VPS53 were set to 24577744; 2920088
Phenotypes for gene: VPS53 were set to Pontocerebellar hypoplasia, type 2E, 615851; Progressive cerebello-cerebral atrophy
VPS53 was added to Intellectual disability panel. Sources: Literature
VPS53 was created by Zornitza Stark
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.