GeneBe

OCRL

protein-coding

OCRL inositol polyphosphate-5-phosphatase, the group of Phosphoinositide phosphatases

Gene summary

This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

MANE transcript

NM_000276.4

Inheritance

XL

ClinVar variants

P:153U:396B:239

Top phenotype

Dent disease 2; Lowe syndrome

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chrX:129,539,849-129,592,561

External References & Databases

Ensembl (ENSG00000122126)NCBI Gene (4952)OMIM (300535)HGNC:8108GenCCUniProt (Q01968)AlphaFoldClinVar (OCRL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~52.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculocerebrorenal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: G2P

Dent disease type 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010359

Submitter: Ambry Genetics

oculocerebrorenal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: ClinGen

OCRL was first reported in related to X-linked Lowe oculocerebrorenal syndrome in 1992 (Attree et al., 1992, PMID: 1321346). Since then over 200 variants have been reported in patients affected by this disease. More than half of these variants are proven or predicted null alleles and some missense variants have also been confirmed to cause deficient enzyme activity by functional studies, indicating a loss-of-function disease mechanism. This gene-disease relationship is further supported by expression studies, animal models, and rescue experiments. In summary, OCRL is definitively associated with X-linked Lowe oculocerebrorenal syndrome.

oculocerebrorenal syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: Labcorp Genetics (formerly Invitae)

oculocerebrorenal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Dent disease type 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010359

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Dent disease type 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010359

Submitter: Labcorp Genetics (formerly Invitae)

oculocerebrorenal syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: PanelApp Australia

Dent disease type 2SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010359

Submitter: Orphanet

oculocerebrorenal syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: Ambry Genetics

Dent disease type 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010359

Submitter: G2P

oculocerebrorenal syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010645

Submitter: Orphanet

Clinical Genomic Database (CGD)

Dent disease 2; Lowe syndromeXL

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Pharmacogenomic; Renal

Rationale: In Dent disease, surveillance and treatment related to manifestations such as hypercalciuria in order to prevent kidney stones, nephrocalcinosis, and to delay the progression of kidney dysfunction may be beneficial (though efficacy is unclear, treatment may include thiazide diuretics, ACE inhibitors, and ARBs); Vitamin D and phosphorous may be beneficial related to skeletal manifestations; Growth hormone may be indicated; Nephrotoxic agents (eg, NSAIDs, aminoglycosides) should be avoided; In Lowe syndrome, which may represent the severe end of of the spectrum of variant-positive individuals, similar treatment related to renal manifestations may be beneficial, as well as care related to other organ systems

Refs: 8504307; 9199559; 9632163; 9682219; 199559; 9917791; 10364518; 0923037; 10767176; 15627218; 17162149; 19390221; 21031565Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OCRL variants in ClinVar

15 Conditions Cataloged
Lowe syndromeTotal: 711
not providedTotal: 158
Dent disease type 2Total: 96
Nephrolithiasis/nephrocalcinosisTotal: 83
not specifiedTotal: 44
OCRL-related disorderTotal: 29
Dent diseaseTotal: 3
Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000276.4. 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.

EffectPLPVUSLBBSum
synonymous
28
clinvar
167
clinvar
8
clinvar
 203
missense
13
clinvar
25
clinvar
325
clinvar
61
clinvar
1
clinvar
 425
nonsense
23
clinvar
8
clinvar
14
clinvar
 45
start loss
0
frameshift
36
clinvar
16
clinvar
1
clinvar
 53
splice donor/acceptor (+/-2bp)
11
clinvar
21
clinvar
28
clinvar
1
clinvar
1
clinvar
 62
Total837039622910788

Highest pathogenic variant AF is 0.000003311568

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000276.4RefSeqNP_000267.224MANE Select
ENST00000371113.9EnsemblENSP00000360154.424MANE Select
NM_001318784.2RefSeqNP_001305713.124Standard
NM_001587.4RefSeqNP_001578.223Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
ocrlDanio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Inositol phosphate metabolism - Homo sapiens (human)
  • Phosphatidylinositol signaling system - Homo sapiens (human)
  • Golgi Associated Vesicle Biogenesis
  • Clathrin derived vesicle budding
  • trans-Golgi Network Vesicle Budding

Biological Process

  • lipid metabolic process
  • phosphatidylinositol biosynthetic process
  • signal transduction
  • phosphatidylinositol-3-phosphate biosynthetic process
  • regulation of GTPase activity

Molecular Function

  • phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
  • GTPase activator activity
  • protein binding
  • phosphatidylinositol phosphate 4-phosphatase activity
  • phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity

Cellular Component

  • photoreceptor outer segment
  • nucleus
  • cytoplasm
  • early endosome
  • Golgi stack

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371113
Coding exons
24
Length
52713
Individuals with no LoFs
125734
Homozygous LoFs
1
Heterozygous LoFs
1
Defined
125736
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.961943500.5540.00002746016
Missense (PolyPhen)45140.190.320992487
Synonymous0.4901111180.9430.000008591633
Loss of Function5.62240.70.04920.00000331619

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000760.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Also converts inositol 1,4,5- trisphosphate to inositol 1,4-bisphosphate and inositol 1,3,4,5- tetrakisphosphate to inositol 1,3,4-trisphosphate (PubMed:25869668, PubMed:7761412, PubMed:9430698). May function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. Involved in primary cilia assembly (PubMed:22228094, PubMed:22543976). {ECO:0000269|PubMed:22228094, ECO:0000269|PubMed:22543976, ECO:0000269|PubMed:25869668, ECO:0000269|PubMed:7761412, ECO:0000269|PubMed:9430698}.;
Disease
DISEASE: Lowe oculocerebrorenal syndrome (OCRL) [MIM:309000]: X- linked multisystem disorder affecting eyes, nervous system, and kidney. It is characterized by hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, aminoaciduria, and reduced ammonia production by the kidney. Ocular abnormalities include cataract, glaucoma, microphthalmos, and decreased visual acuity. Developmental delay, hypotonia, behavior abnormalities, and areflexia are also present. Renal tubular involvement is characterized by impaired reabsorption of bicarbonate, amino acids, and phosphate. Musculoskeletal abnormalities such as joint hypermobility, dislocated hips, and fractures may develop as consequences of renal tubular acidosis and hypophosphatemia. Cataract is the only significant manifestation in carriers and is detected by slit-lamp examination. {ECO:0000269|PubMed:10767176, ECO:0000269|PubMed:10923037, ECO:0000269|PubMed:19168822, ECO:0000269|PubMed:20133602, ECO:0000269|PubMed:21031565, ECO:0000269|PubMed:21233288, ECO:0000269|PubMed:9199559, ECO:0000269|PubMed:9632163, ECO:0000269|PubMed:9682219, ECO:0000269|PubMed:9788721}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dent disease 2 (DD2) [MIM:300555]: A renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Characteristic abnormalities include low-molecular-weight proteinuria and other features of Fanconi syndrome, such as glycosuria, aminoaciduria, and phosphaturia, but typically do not include proximal renal tubular acidosis. Progressive renal failure is common, as are nephrocalcinosis and kidney stones. {ECO:0000269|PubMed:15627218, ECO:0000269|PubMed:17384968, ECO:0000269|PubMed:21031565}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0972

Intolerance Scores

LoFtool
0.00744
RVIS EVS
-0.25
RVIS percentile EVS
35.99

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.546

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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