GDI1

protein-coding

GDP dissociation inhibitor 1

Gene summary

GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI1 is expressed primarily in neural and sensory tissues. Mutations in GDI1 have been linked to X-linked nonspecific cognitive disability. [provided by RefSeq, Jul 2008]

Previous symbols:

MRX48
MRX41
GDIL

MANE transcript

NM_001493.3

Inheritance

ClinVar variants

P:16U:164B:49

Top phenotype

Intellectual developmental disorder, X-linked 41

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:154,436,913-154,443,467

External References & Databases

Ensembl (ENSG00000203879)

Transcript & Mutation Effects

hg38 • Region Span ~6.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 41LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010451

Submitter: G2P

intellectual developmental disorder, X-linked 41MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010451

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 41STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010451

Submitter: Labcorp Genetics (formerly Invitae)

non-syndromic X-linked intellectual disabilityMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

*GDI1* was first reported in relation to non-syndromic X-linked intellectual disability in 1996 (Hamel et al., PMID: 8826463). Frequently reported phenotypic features in males include intellectual disability varying from mild to severe. Female carriers range from mild intellectual disability to intellect in the normal range. Five variants (missense, protein truncating, and frameshift) that have been reported in five probands in six publications (PMIDs: 8826463, 9106537, 9620768, 9668174, 22002931, and 28863211) are included in this curation. For four of the reported probands, segregation scoring was included based on published LOD scores within the appropriate articles. The mechanism of pathogenicity is most likely loss of function. The gene-disease relationship is also supported by animal models and functional alteration data (PMIDs: 9620768, 20159109, 22291894, and 10473636). *GDI1* knockout mouse models showed behavioral features consistent with neurodevelopmental disorders such as impaired short term memory, altered social behavior, cognitive impairment in mazes, and impaired attention (PMID: 9620768). Rat-derived neurons treated with *GDI1* knockdown antisense oligonucleotides had reduced growth and function, suggesting *GDI1* plays an important role in neurodevelopment (PMIDs: 9620768 and 10473636). This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on May 24, 2018 (SOP Version 5). It was reevaluated on April 27, 2023 (SOP Version 10). As a result of this reevaluation, the classification did not change. This gene-disease pair remains classified as moderate due to limited reported variants. Additionally, the reported phenotypes have been nonspecific and testing has been targeted to X-linked genes rather than comprehensive exome or genome sequencing.

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 41STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010451

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 41XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8826463; 9106537; 9668174; 9620768; 22002931

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GDI1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 87

Inborn genetic diseasesTotal: 45

not specifiedTotal: 41

Intellectual disability, X-linked 41Total: 28

GDI1-related disorderTotal: 7

Intellectual disabilityTotal: 2

Immunodeficiency 47Total: 1

Non-syndromic X-linked intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001493.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			17 clinvar	36 clinvar	2 clinvar	55
missense	1 clinvar	4 clinvar	115 clinvar	11 clinvar		131
nonsense	1 clinvar	1 clinvar	6 clinvar			8
start loss						0
frameshift	5 clinvar	2 clinvar				7
splice donor/acceptor (+/-2bp)		2 clinvar	26 clinvar			28
Total	7	9	164	47	2	229

Highest pathogenic variant AF is 0.0000027373662

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001493.3	RefSeq	NP_001484.1	11	MANE Select
ENST00000447750.7	Ensembl	ENSP00000394071.2	11	MANE Select
ENST00000415109.5	Ensembl	ENSP00000396215.1	2	Standard
ENST00000445564.5	Ensembl	ENSP00000394752.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrated Breast Cancer Pathway
Signal Transduction
Vesicle-mediated transport
Membrane Trafficking
Rho GTPase cycle

Biological Process

signal transduction
protein transport
Rab protein signal transduction
positive regulation of GTPase activity
positive regulation of axon extension

Molecular Function

GDP-dissociation inhibitor activity
Rab GDP-dissociation inhibitor activity
GTPase activator activity
protein binding
Rab GTPase binding

Cellular Component

cytoplasm
Golgi apparatus
cytosol
axon
midbody

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447750
Coding exons: 11
Length: 6549
Individuals with no LoFs: 125536
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125537
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.29	70	201	0.348	0.0000180	2966
Missense (PolyPhen)		3	67.794	0.044252		992
Synonymous	-1.73	101	81.1	1.25	0.00000750	840
Loss of Function	3.65	0	15.6	0.00	0.00000115	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Promotes the dissociation of GDP-bound Rab proteins from the membrane and inhibits their activation. Promotes the dissociation of RAB1A, RAB3A, RAB5A and RAB10 from membranes. {ECO:0000269|PubMed:23815289}.;

Recessive Scores

pRec: 0.184

Intolerance Scores

RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Medium
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Medium	Medium