Ophthalmological ciliopathies

Gene: ARL3

Green List (high evidence)

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

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 12:36 p.m. | Last Modified: 30 Jan 2023, 12:36 p.m.
Panel Version: 2.6

Ivone Leong (Genomics England Curator)

Comment on mode of inheritance: MOI changed from Biallelic to Both monoallelic and biallelic as eye phenotype is seen for both MOIs.
Created: 18 Oct 2021, 10:43 a.m. | Last Modified: 18 Oct 2021, 10:43 a.m.
Panel Version: 1.22
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

Phenotypes
Joubert syndrome 35 MIM#61816

Publications

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

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • NHS GMS
  • Expert Review Green
  • Expert list
Phenotypes
  • Joubert syndrome 35, OMIM:61816
  • cone-rod dystrophy, MONDO:0015993
  • Retinitis pigmentosa 83, OMIM:618173
OMIM
604695
Clinvar variants
Variants in ARL3
Penetrance
None
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q4_21_rating was removed from gene: ARL3.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Green was added to ARL3. Source NHS GMS was added to ARL3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

18 Oct 2021, Gel status: 2

Set mode of inheritance

Ivone Leong (Genomics England Curator)

Mode of inheritance for gene: ARL3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

18 Oct 2021, Gel status: 2

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: ARL3 were changed from Joubert syndrome 35, OMIM:61816 to Joubert syndrome 35, OMIM:61816; cone-rod dystrophy, MONDO:0015993; Retinitis pigmentosa 83, OMIM:618173

18 Oct 2021, Gel status: 2

Removed Tag, Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist was removed from gene: ARL3. Tag Q4_21_rating tag was added to gene: ARL3.

18 Oct 2021, Gel status: 2

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

Ivone Leong (Genomics England Curator)

gene: ARL3 was added gene: ARL3 was added to Ophthalmological ciliopathies. Sources: Expert list,Expert Review Amber watchlist tags were added to gene: ARL3. Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL3 were set to 30269812; 16565502; 33748123; 31743939; 26964041; 30932721; 34485303 Phenotypes for gene: ARL3 were set to Joubert syndrome 35, OMIM:61816