OCRL p.Arg318Cys

Variant names:

• chrX-129562396-C-T
• rs137853263
• NM_000276.4:c.952C>T
• OCRL p.Arg318Cys

Your query was ambiguous. Multiple possible variants found:

• chrX-129562396-C-T
• chrX-129562396-CGC-TGT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000276.4(OCRL):​c.952C>T​(p.Arg318Cys) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005329372: Experimental studies reveals that this missense change affects the function of OCRL gene (Rodrick et. al., 2015).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 7.56
• Publications: 25 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, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• oculocerebrorenal syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005329372: Experimental studies reveals that this missense change affects the function of OCRL gene (Rodrick et. al., 2015).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-129562396-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 562272.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-129562396-C-T is Pathogenic according to our data. Variant chrX-129562396-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000276.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	NM_000276.4	MANE Select	c.952C>T	p.Arg318Cys	missense	Exon 11 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.955C>T	p.Arg319Cys	missense	Exon 11 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.952C>T	p.Arg318Cys	missense	Exon 11 of 23	NP_001578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.952C>T	p.Arg318Cys	missense	Exon 11 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.952C>T	p.Arg318Cys	missense	Exon 11 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.949C>T	p.Arg317Cys	missense	Exon 11 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Dent disease type 2 (3)
1	-	-	Lowe syndrome;C1845167:Dent disease type 2 (1)
1	-	-	not provided (1)
1	-	-	OCRL-related disorder (1)
-	-	-	Lowe syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.97
gMVP		0.93
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs137853263;

hg19: chrX-128696373;

COSMIC: COSV63980555;

COSMIC: COSV63980555;