Intellectual disability syndromic and non-syndromic
Gene: RAB1A Green List (high evidence)Green List (high evidence)
PMID: 37924809 2 families with PTCs inherited from affected fathers (Arg175* and Thr43fs), another proband with a PTC and unknown inheritance (Val22fs) and a 4th proband with a de novo missense (Leu28Pro). All variants were absent from gnomad except Val22fs which has a PTC within the first 102 nucleotides so is likely to escape NMD. Arg175* was in the last exon and also escapes NMD and removes two C-terminal prenylated cysteine residues that direct the subcellular localization and activity of Rab proteins. Studies in transfected cells showed a construct truncated protein failed to localise to the golgi. In KO cells both Arg175* and Leu28pro failed to rescue the phenotype.
The individual with the missense variant had a more severe phenotype involving abnormal MRI findings and spondyloepimetaphyseal dysplasia, the functional studies suggested this variant has a dominant negative effect which would explain this.
PMID: 38091987: two new probands with NDD and spasticity. One de novo for Ser200*, 2nd patient de novo for Arg175* same variant previously identified in a family from the previous paper. This new paper also says they have an aditional 3rd family with 2 affected siblings and an affected mother who also have Arg175*.Created: 13 Mar 2026, 4:16 p.m. | Last Modified: 13 Mar 2026, 4:19 p.m.
Panel Version: 1.4516
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
neurodevelopmental disorder MONDO:0700092, RAB1A-related
Publications
I don't know
4 families and 5 individuals, 2/5 have speech delay and 4/5 have motor delay.
Anxiety in 3/5 and autism in 2/5. Microcephaly in only one individual, spastic paraplegia observed in 2 individuals from one family.
In 2 families variants were inherited from an affected parent.
Sources: LiteratureCreated: 7 Dec 2023, 1:11 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
neurodevelopmental disorder MONDO:0700092, CASP2-related
Publications
Publications for gene: RAB1A were set to PMID: 37924809
Gene: rab1a has been classified as Green List (High Evidence).
Gene: rab1a has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: RAB1A were changed from neurodevelopmental disorder MONDO:0700092, CASP2-related to neurodevelopmental disorder MONDO:0700092, RAB1A-related
Gene: rab1a has been classified as Amber List (Moderate Evidence).
gene: RAB1A was added gene: RAB1A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature Mode of inheritance for gene: RAB1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB1A were set to PMID: 37924809 Phenotypes for gene: RAB1A were set to neurodevelopmental disorder MONDO:0700092, CASP2-related Review for gene: RAB1A 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 panelapp@genomicsengland.co.uk
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.