rs137853858

Variant names:

• chrX-129569374-C-T
• rs137853858
• NM_000276.4:c.1577C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000276.4(OCRL):​c.1577C>T​(p.Pro526Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P526S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.56
• Publications: 2 publications found

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) 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]

OCRL Gene-Disease associations (from GenCC):

• Dent disease type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000276.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-129569373-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-129569374-C-T is Pathogenic according to our data. Variant chrX-129569374-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68720.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.1577C>T	p.Pro526Leu	missense_variant	Exon 15 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.1580C>T	p.Pro527Leu	missense_variant	Exon 15 of 24		NP_001305713.1
OCRL	NM_001587.4	c.1577C>T	p.Pro526Leu	missense_variant	Exon 15 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.1577C>T	p.Pro526Leu	missense_variant	Exon 15 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.1577C>T	p.Pro526Leu	missense_variant	Exon 15 of 23	1		ENSP00000349635.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome Pathogenic:1 Other:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 526 of the OCRL protein (p.Pro526Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lowe syndrome (PMID: 10767176). This variant is also known as c.1754C>T. ClinVar contains an entry for this variant (Variation ID: 68720). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OCRL protein function with a positive predictive value of 95%. This variant disrupts the p.Pro526 amino acid residue in OCRL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19902262; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.95		Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);
MVP		1.0
MPC		2.4
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.97
gMVP		1.0
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853858; hg19: chrX-128703351;