rs1556346316

Positions:

• chrX-129562444-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000276.4(OCRL):​c.1000C>T​(p.Arg334Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.95

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-129562444-C-T is Pathogenic according to our data. Variant chrX-129562444-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 500705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-129562444-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCRL	NM_000276.4	c.1000C>T	p.Arg334Ter	stop_gained	11/24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.1003C>T	p.Arg335Ter	stop_gained	11/24		NP_001305713.1
OCRL	NM_001587.4	c.1000C>T	p.Arg334Ter	stop_gained	11/23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.1000C>T	p.Arg334Ter	stop_gained	11/24	1	NM_000276.4	ENSP00000360154	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lowe syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 06, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in OCRL are known to be pathogenic (PMID: 21031565, 22381590). This variant has been observed to segregate with Lowe syndrome in a family (PMID: 10364518) and is present in individuals with Lowe syndrome (PMID: 25480730, 28973083). ClinVar contains an entry for this variant (Variation ID: 500705). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg334*) in the OCRL gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.16	N
MutationTaster	Benign	1.0	A;A
Vest4		0.78
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1556346316; hg19: chrX-128696421; COSMIC: COSV63980169; COSMIC: COSV63980169;