Intellectual disability - microarray and sequencing
Gene: RAP1GDS1 Amber List (moderate evidence)Comment on list classification: Promoting this gene from red to amber. There are now 4 families reported with the same splice site variant and a similar phenotype but intellectual disability is not seen in all probands. 2 of the families come from the same region. The ancestry of the other 2 families is not known. There is one additional case with a different 1bp deletion variant in RAP1GDS1 is also reported with ID as part of the phenotype. The expert reviewer proposes this gene should be green, and it also green on the PanelApp Australia Intellectual disability panel. Therefore the recommendation is for GREEN rating following GMS consideration and expert review.Created: 10 Aug 2022, 11:21 a.m. | Last Modified: 10 Aug 2022, 11:21 a.m.
Panel Version: 3.1661
PMID: 33875846 - Bertoli-Avella et al 2021 - report 4 new patients with variants in RAP1GDS1 from 3 families. In two families the previously reported splice site variant c.1444-1G>A is found in a homozygous state. In one of these families the patient is reported to have motor delay and spastic paraplegia but no intellectual disability. In the other family, 2 siblings with this variant a phenotype that includes movement difficulties and hypotonia, and global developmental delay in one sibling. Exon 13 skipping was detected in blood mRNA from the patients. In the third family a different homozgyous variant (c.83delT, p.Leu28fs) and a phenotype that includes movement difficulties, hypotonia and global developmental delay. The ethnicity of the patients is not given.Created: 10 Aug 2022, 11:14 a.m. | Last Modified: 10 Aug 2022, 11:14 a.m.
Panel Version: 3.1660
Green List (high evidence)
Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap those reported in PMID: 32431071.
Created: 30 Oct 2021, 11:54 a.m. | Last Modified: 30 Oct 2021, 11:56 a.m.
Panel Version: 3.1396
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability, developmental delay
Publications
I don't know
After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Comment on list classification: The same variant identified in two families from the region, indicating a possible founder effect. Therefore rated Red as there is not currently enough evidence that other variants in the RAP1GDS1 gene are disease causing.Created: 27 Aug 2020, 12:39 p.m. | Last Modified: 27 Aug 2020, 12:39 p.m.
Panel Version: 3.270
PMID: 32431071 (2020) - The same homozygous splice acceptor site variant was identified in four patients from two consanguineous Saudi families with ID, global DD, and hypotonia. The variant segregated with the disorder in both families and RT‐PCR analysis confirmed aberrant splicing and decreased mRNA expression, but no further functional studies were performed.Created: 27 Aug 2020, 12:36 p.m. | Last Modified: 27 Aug 2020, 12:36 p.m.
Panel Version: 3.269
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; Global developmental delay; Hypotonia
Publications
I don't know
Four individuals from two consanguineous families, same homozygous splice site variant detected, borderline Red/Amber.
Sources: LiteratureCreated: 6 Jul 2020, 7:27 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; dysmorphic features
Publications
Tag Q3_22_rating was removed from gene: RAP1GDS1. Tag Q3_22_expert_review was removed from gene: RAP1GDS1.
Tag Q3_22_rating tag was added to gene: RAP1GDS1. Tag Q3_22_expert_review tag was added to gene: RAP1GDS1.
Gene: rap1gds1 has been classified as Amber List (Moderate Evidence).
Tag founder-effect tag was added to gene: RAP1GDS1.
Gene: rap1gds1 has been classified as Red List (Low Evidence).
gene: RAP1GDS1 was added gene: RAP1GDS1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RAP1GDS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAP1GDS1 were set to 32431071 Phenotypes for gene: RAP1GDS1 were set to Intellectual disability; dysmorphic features Review for gene: RAP1GDS1 was set to AMBER
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.