OCRL

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

Basic information

Region (hg38): X:129539849-129592561

Links

ENSG00000122126 ∙ NCBI:4952 ∙ OMIM:300535 ∙ HGNC:8108 ∙ Uniprot:Q01968 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• oculocerebrorenal syndrome (Definitive), mode of inheritance: XLR
• Dent disease type 2 (Definitive), mode of inheritance: XLR
• oculocerebrorenal syndrome (Strong), mode of inheritance: XL
• oculocerebrorenal syndrome (Definitive), mode of inheritance: XL
• Dent disease type 2 (Definitive), mode of inheritance: XL
• oculocerebrorenal syndrome (Supportive), mode of inheritance: XL
• Dent disease type 2 (Supportive), mode of inheritance: XL
• Dent disease type 2 (Strong), mode of inheritance: XL
• oculocerebrorenal syndrome (Definitive), mode of inheritance: XL
• oculocerebrorenal syndrome (Definitive), mode of inheritance: XL
• Dent disease type 2 (Definitive), mode of inheritance: XL
• Dent disease type 2 (Strong), mode of inheritance: XL
• oculocerebrorenal syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dent disease 2; Lowe syndrome	XL	Pharmacogenomic; Renal	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	Musculoskeletal; Neurologic; Ophthalmologic; Renal	8504307; 9199559; 9632163; 9682219; 199559; 9917791; 10364518; 0923037; 10767176; 15627218; 17162149; 19390221; 21031565

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the OCRL gene.

• Lowe syndrome (43 variants)
• not provided (23 variants)
• Dent disease type 2 (3 variants)
• Nephrolithiasis/nephrocalcinosis (1 variants)
• OCRL-related disorder (1 variants)
• Lowe syndrome;Dent disease type 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the OCRL gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	132	7	141
missense	6	16	123	37	3	185
nonsense	19	4	1			24
start loss						0
frameshift	25	9				34
inframe indel	1		3			4
splice donor/acceptor (+/-2bp)	8	15			1	24
splice region			20	39	5	64
non coding	1	1	1	120	33	156
Total	60	45	130	289	44

Variants in OCRL

This is a list of pathogenic ClinVar variants found in the OCRL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-129539976-AAT-A			Benign (Nov 06, 2019)
X-129539976-A-AAT			Benign (Jan 06, 2020)
X-129539976-A-AATAT			Benign (Apr 04, 2020)
X-129539976-A-AATATATAT			Likely benign (Dec 19, 2020)
X-129539986-TA-T			Likely benign (May 05, 2020)
X-129540157-C-T			Benign (Jul 27, 2018)
X-129540176-C-T			Benign (Jul 27, 2018)
X-129540450-C-T		Lowe syndrome;Dent disease type 2 • Lowe syndrome • Nephrolithiasis/nephrocalcinosis	Likely benign (Jan 14, 2024)
X-129540451-G-C		Lowe syndrome	Likely benign (May 08, 2023)
X-129540454-C-G		Lowe syndrome	Likely benign (Sep 27, 2022)
X-129540456-C-G		Lowe syndrome	Likely benign (Jan 30, 2024)
X-129540456-C-T		Lowe syndrome	Likely benign (Jul 16, 2023)
X-129540457-G-A			Likely benign (Jan 01, 2023)
X-129540458-G-T		Intellectual disability	Uncertain significance (Jan 16, 2020)
X-129540460-C-T		Lowe syndrome	Likely benign (Dec 14, 2023)
X-129540464-G-A			Uncertain significance (Feb 17, 2017)
X-129540466-C-T		Lowe syndrome	Likely benign (May 13, 2023)
X-129540468-A-T		Lowe syndrome	Uncertain significance (Dec 22, 2023)
X-129540472-G-A		Lowe syndrome	Likely benign (Jan 04, 2024)
X-129540486-C-T		Lowe syndrome • OCRL-related disorder	Likely benign (Dec 20, 2023)
X-129540487-C-G		Lowe syndrome	Likely benign (Jan 28, 2024)
X-129540488-G-A		Lowe syndrome • not specified • OCRL-related disorder	Conflicting classifications of pathogenicity (Jan 29, 2024)
X-129540492-A-C		Lowe syndrome	Likely benign (Feb 10, 2023)
X-129540492-AGAAG-A		Lowe syndrome	Likely benign (Apr 10, 2023)
X-129540493-G-A		Lowe syndrome	Likely benign (Apr 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
OCRL	protein_coding	protein_coding	ENST00000371113	24	52713

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000119	125734	1	1	125736	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.96	194	350	0.554	0.0000274	6016
Missense in Polyphen		45	140.19	0.32099		2487
Synonymous	0.490	111	118	0.943	0.00000859	1633
Loss of Function	5.62	2	40.7	0.0492	0.00000331	619

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000760	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000122	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Signal Transduction;D-<i>myo</i>-inositol (1,3,4)-trisphosphate biosynthesis;superpathway of D-<i>myo</i>-inositol (1,4,5)-trisphosphate metabolism;Vesicle-mediated transport;Membrane Trafficking;Metabolism of lipids;1D-<i>myo</i>-inositol hexakisphosphate biosynthesis II (mammalian);Inositol phosphate metabolism;3-phosphoinositide degradation;D-<i>myo</i>-inositol (1,4,5)-trisphosphate degradation;Metabolism;superpathway of inositol phosphate compounds;Rho GTPase cycle;Phosphatidylinositol phosphate metabolism;Signaling by Rho GTPases;Clathrin-mediated endocytosis;Synthesis of IP3 and IP4 in the cytosol;Inositol phosphate metabolism;Synthesis of PIPs at the Golgi membrane;Synthesis of PIPs at the plasma membrane;PI Metabolism;Phospholipid metabolism;Synthesis of IP2, IP, and Ins in the cytosol (Consensus)

Recessive Scores

• pRec: 0.0972

Intolerance Scores

• loftool: 0.00744
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.99

Haploinsufficiency Scores

• pHI: 0.334
• hipred: Y
• hipred_score: 0.853
• ghis: 0.572

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.546

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ocrl
• Phenotype: homeostasis/metabolism phenotype; growth/size/body region phenotype; renal/urinary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype

Zebrafish Information Network

• Gene name: ocrl
• Affected structure: melanocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: lipid metabolic process;phosphatidylinositol biosynthetic process;signal transduction;phosphatidylinositol-3-phosphate biosynthetic process;regulation of GTPase activity;positive regulation of GTPase activity;inositol phosphate metabolic process;inositol phosphate dephosphorylation;phosphatidylinositol dephosphorylation;regulation of small GTPase mediated signal transduction;cilium assembly;membrane organization
• Cellular component: photoreceptor outer segment;nucleus;cytoplasm;early endosome;Golgi stack;Golgi-associated vesicle;trans-Golgi network;cytosol;plasma membrane;clathrin-coated pit;membrane;clathrin-coated vesicle;phagocytic vesicle membrane;early endosome membrane
• 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;Rac GTPase binding;inositol-1,4,5-trisphosphate 5-phosphatase activity;inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity;inositol phosphate phosphatase activity