ARL13B

protein-coding

ADP ribosylation factor like GTPase 13B, the group of ARF GTPase family

Gene summary

This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

Previous symbols:

ARL2L1

MANE transcript

NM_001174150.2

Inheritance

ClinVar variants

P:49U:168B:89

Top phenotype

Joubert syndrome 8

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr3:93,980,139-94,055,678

External References & Databases

Ensembl (ENSG00000169379)

Transcript & Mutation Effects

hg38 • Region Span ~75.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012855

Submitter: Natera

Joubert syndrome 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012855

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: ClinGen

ARL13B was first reported in relation to autosomal recessive Joubert syndrome in 2008 (Cantagrel et al., 18674751). At least 11 unique variants (missense, nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 8 probands in 5 publications (PMIDs: 18674751, 26092869, 25138100, 27894351, 29255182). Variants in this gene segregated with disease in 4 additional family members. The mechanism for disease is homozygous loss of function. This gene-disease association is supported by animal models, rescue experiments, expression studies, and in vitro functional assays. In summary, ARL13B is definitively associated with autosomal recessive Joubert syndrome. This classification was approved by the ClinGen Syndromic Disorders GCEP on 6.3.2020 (SOP Version 7).

Joubert syndrome 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012855

Submitter: G2P

Joubert syndrome 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012855

Submitter: PanelApp Australia

Joubert syndrome 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012855

Submitter: Ambry Genetics

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Clinical Genomic Database (CGD)

Joubert syndrome 8AR

Manifestation: Neurologic; Ophthalmologic; Renal

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

Comments: The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial

Refs: 18674751; 20615230; 22241855; 25138100

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARL13B variants in ClinVar

9 Conditions Cataloged

Joubert syndrome 8Total: 339

not specifiedTotal: 104

not providedTotal: 65

Inborn genetic diseasesTotal: 49

ARL13B-related disorderTotal: 32

Joubert syndrome and related disordersTotal: 9

Joubert syndromeTotal: 3

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001174150.2. 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			2 clinvar	72 clinvar	1 clinvar	75
missense	1 clinvar	7 clinvar	162 clinvar	15 clinvar	1 clinvar	186
nonsense	4 clinvar	8 clinvar				12
start loss						0
frameshift	5 clinvar	18 clinvar				23
splice donor/acceptor (+/-2bp)		6 clinvar	4 clinvar			10
Total	10	39	168	87	2	306

Highest pathogenic variant AF is 0.00018281832

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001174150.2	RefSeq	NP_001167621.1	10	MANE Select
ENST00000394222.8	Ensembl	ENSP00000377769.3	10	MANE Select
NM_001174151.2	RefSeq	NP_001167622.1	8	Standard
NM_001321328.2	RefSeq	NP_001308257.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arl13b	Danio rerio	Structure: neuromast hair cell Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

arl13b

Danio rerio

Structure: neuromast hair cell

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

ARL13B-mediated ciliary trafficking of INPP5E
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

heart looping
smoothened signaling pathway
dorsal/ventral pattern formation
response to lithium ion
neural tube patterning

Molecular Function

protein binding
GTP binding

Cellular Component

cilium
axoneme
motile cilium
ciliary membrane
non-motile cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394222
Coding exons: 10
Length: 75530
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0592	230	227	1.01	0.0000113	2794
Missense (PolyPhen)		59	62.602	0.94246		746
Synonymous	-0.270	81	78.0	1.04	0.00000375	778
Loss of Function	1.42	17	24.6	0.691	0.00000122	308

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cilium-specific protein required to control the microtubule-based, ciliary axoneme structure. May act by maintaining the association between IFT subcomplexes A and B. Binds GTP but is not able to hydrolyze it; the GTPase activity remains unclear. Required to pattern the neural tube. Involved in cerebral cortex development: required for the initial formation of a polarized radial glial scaffold, the first step in the construction of the cerebral cortex, by regulating ciliary signaling. Regulates the migration and placement of postmitotic interneurons in the developing cerebral cortex. May regulate endocytic recycling traffic; however, additional evidences are required to confirm these data. {ECO:0000269|PubMed:23150559}.;
Disease: DISEASE: Joubert syndrome 8 (JBTS8) [MIM:612291]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:18674751, ECO:0000269|PubMed:25138100}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0996

Intolerance Scores

LoFtool: 0.934
RVIS EVS: -0.05
RVIS percentile EVS: 50.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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