Neurological ciliopathies

Gene: ARL3

Amber List (moderate evidence)

ARL3 (ADP ribosylation factor like GTPase 3)
EnsemblGeneIds (GRCh38): ENSG00000138175
EnsemblGeneIds (GRCh37): ENSG00000138175
OMIM: 604695, Gene2Phenotype
ARL3 is in 4 panels

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene submitted by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome).

As there are only 2 cases that have been associated with Joubert syndrome (PMID:30269812) and the knockout mouse model does not appear to have a neurological phenotype (PMID:16565502) this gene has been given an Amber rating until further evidence is available.
Created: 18 Oct 2021, 10:32 a.m. | Last Modified: 18 Oct 2021, 10:32 a.m.
Panel Version: 1.20
Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.

PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.

PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.

PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.

PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.

PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Created: 18 Oct 2021, 10:29 a.m. | Last Modified: 18 Oct 2021, 10:29 a.m.
Panel Version: 1.19

Zornitza Stark (Australian Genomics)

Green List (high evidence)

4 individuals from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Sources: Expert list
Created: 25 May 2020, 2:24 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Joubert syndrome 35 MIM#61816


Variants in this GENE are reported as part of current diagnostic practice


Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Amber
  • Joubert syndrome 35, OMIM:61816
Clinvar variants
Variants in ARL3
Panels with this gene

History Filter Activity

18 Oct 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: arl3 has been classified as Amber List (Moderate Evidence).

18 Oct 2021, Gel status: 0

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: ARL3.

18 Oct 2021, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: ARL3 were set to 30269812; 16565502

10 Aug 2021, Gel status: 0

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: ARL3 were changed from Joubert syndrome 35 MIM#61816 to Joubert syndrome 35, OMIM:61816

25 May 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: ARL3 was added gene: ARL3 was added to Neurological ciliopathies. Sources: Expert list Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL3 were set to 30269812; 16565502 Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#61816 Review for gene: ARL3 was set to GREEN gene: ARL3 was marked as current diagnostic