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NM_004311.4(ARL3):c.446G>A (p.Arg149His) AND Joubert syndrome 35

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 30, 2018
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000714512.2

Allele description [Variation Report for NM_004311.4(ARL3):c.446G>A (p.Arg149His)]

NM_004311.4(ARL3):c.446G>A (p.Arg149His)

Gene:
ARL3:ARF like GTPase 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q24.32
Genomic location:
Preferred name:
NM_004311.4(ARL3):c.446G>A (p.Arg149His)
HGVS:
  • NC_000010.11:g.102685871C>T
  • NM_004311.4:c.446G>AMANE SELECT
  • NP_004302.1:p.Arg149His
  • NC_000010.10:g.104445628C>T
  • NM_004311.3:c.446G>A
Protein change:
R149H; ARG149HIS
Links:
OMIM: 604695.0002; dbSNP: rs770782663
NCBI 1000 Genomes Browser:
rs770782663
Molecular consequence:
  • NM_004311.4:c.446G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Joubert syndrome 35
Identifiers:
MONDO: MONDO:0032570; MedGen: C4748442; OMIM: 618161

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000845202OMIM
no assertion criteria provided
Pathogenic
(Oct 30, 2018) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition.

Alkanderi S, Molinari E, Shaheen R, Elmaghloob Y, Stephen LA, Sammut V, Ramsbottom SA, Srivastava S, Cairns G, Edwards N, Rice SJ, Ewida N, Alhashem A, White K, Miles CG, Steel DH, Alkuraya FS, Ismail S, Sayer JA.

Am J Hum Genet. 2018 Oct 4;103(4):612-620. doi: 10.1016/j.ajhg.2018.08.015. Epub 2018 Sep 27.

PubMed [citation]
PMID:
30269812
PMCID:
PMC6174286

Details of each submission

From OMIM, SCV000845202.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 3 sisters, born of consanguineous Pakistani parents (family 2), with Joubert syndrome-35 (JBTS35; 618161), Alkanderi et al. (2018) identified a homozygous c.446G-A transition (c.446G-A, NM_004311.3) in the ARL3 gene, resulting in an arg149-to-his (R149H) substitution at a highly conserved residue predicted to interact with ARL13B (608922). The mutation affected the same residue as in another family with the disorder (R149C; 604695.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. In vitro functional expression assays using murine Arl3 showed that the R149H variant disrupted the interaction with ARL13B (608922) and resulted in impaired ARL13B-assisted GTP-nucleotide exchange. Patient fibroblasts did not show abnormal ciliary length or structural appearance, but cilia showed a significant loss of both INPP5E (613037) and NPHP3 (608002) content, indicating that wildtype ARL3 is required for normal release of these cargoes into the ciliary axoneme. There was a defect in both prenylated and myristoylated ciliary cargo delivery compared to wildtype.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024