rs137853260

chrX-129569296-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000276.4(OCRL):c.1499G>A(p.Arg500Gln) 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. 11/19 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. R500G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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-129569295-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92721.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-129569296-G-A is Pathogenic according to our data. Variant chrX-129569296-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.1499G>A	p.Arg500Gln	missense_variant	15/24	ENST00000371113.9
OCRL	NM_001318784.2	c.1502G>A	p.Arg501Gln	missense_variant	15/24
OCRL	NM_001587.4	c.1499G>A	p.Arg500Gln	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.1499G>A	p.Arg500Gln	missense_variant	15/24	1	NM_000276.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lowe syndrome Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	May 09, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 05, 1998	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 500 of the OCRL protein (p.Arg500Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lowe syndrome (PMID: 25480730, 35919034). ClinVar contains an entry for this variant (Variation ID: 10858). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 27, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.96		Loss of MoRF binding (P = 0.0121);Loss of MoRF binding (P = 0.0121);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853260; hg19: chrX-128703273; COSMIC: COSV63980092;