X-129562453-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP5BP4

The NM_000276.4(OCRL):c.1009C>T(p.Arg337Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,207,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

OCRL
NM_000276.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 1.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant X-129562453-C-T is Pathogenic according to our data. Variant chrX-129562453-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68695.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.30643737). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4 link	c.1009C>T	p.Arg337Cys	missense_variant	Exon 11 of 24	ENST00000371113.9	NP_000267.2	Q01968-1
OCRL	NM_001318784.2 link	c.1012C>T	p.Arg338Cys	missense_variant	Exon 11 of 24		NP_001305713.1	Q504W7
OCRL	NM_001587.4 link	c.1009C>T	p.Arg337Cys	missense_variant	Exon 11 of 23		NP_001578.2	Q01968-2A0A2X0TVZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9 link	c.1009C>T	p.Arg337Cys	missense_variant	Exon 11 of 24	1	NM_000276.4	ENSP00000360154.4		Q01968-1
OCRL	ENST00000357121.5 link	c.1009C>T	p.Arg337Cys	missense_variant	Exon 11 of 23	1		ENSP00000349635.5		Q01968-2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33922

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183438

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096161

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361615

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33922

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lowe syndrome

Pathogenic:1Uncertain:1Other:1

Dec 11, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as hemizygous. -

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 337 of the OCRL protein (p.Arg337Cys). This variant is present in population databases (rs137853831, gnomAD 0.004%). This missense change has been observed in individual(s) with Lowe Syndrome (PMID: 21031565). ClinVar contains an entry for this variant (Variation ID: 68695). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OCRL c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase (IPR000300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1009C>T has been reported in the literature in an individual affected with Lowe Disease (example: Hichri_2011). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (example: Hichri_2011). The following publication has been ascertained in the context of this evaluation (PMID: 21031565). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.31

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.046

D;D

Polyphen

0.018

B;B

Vest4

0.20

MutPred

0.63

Loss of MoRF binding (P = 0.0168);Loss of MoRF binding (P = 0.0168);

MVP

0.94

MPC

1.5

ClinPred

0.68

GERP RS

4.7

Varity_R

0.39

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over