X-129562396-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000371113.9(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 (★★). 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
ENST00000371113.9 missense

Scores

14
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:2

Conservation

PhyloP100: 7.56
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-129562397-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1455667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 [Likely_pathogenic]. Clinvar id is 10861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OCRLNM_000276.4 linkuse as main transcriptc.952C>T p.Arg318Cys missense_variant 11/24 ENST00000371113.9 NP_000267.2
OCRLNM_001318784.2 linkuse as main transcriptc.955C>T p.Arg319Cys missense_variant 11/24 NP_001305713.1
OCRLNM_001587.4 linkuse as main transcriptc.952C>T p.Arg318Cys missense_variant 11/23 NP_001578.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OCRLENST00000371113.9 linkuse as main transcriptc.952C>T p.Arg318Cys missense_variant 11/241 NM_000276.4 ENSP00000360154 P1Q01968-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dent disease type 2 Pathogenic:2Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 06, 2021- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMay 20, 2023The missense variant c.952C>T(p.Arg318Cys) in OCRL gene has been reported in individuals affected with dent disease (Zhang et al. 2022; Rodrick et. al., 2015). Experimental studies reveals that this missense change affects the function of OCRL gene (Rodrick et. al., 2015). The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar databaseas Likely Pathogenic. The amino acid change p.Arg318Cys in OCRL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Arg at position 318 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 20, 2017- -
OCRL-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 25, 2024The OCRL c.952C>T variant is predicted to result in the amino acid substitution p.Arg318Cys. This variant has been repeatedly reported in individuals with Dent disease (reported as R301C in Hoopes et al. 2005. PubMed ID: 15627218; Hichri et al. 2011. PubMed ID: 21031565; Bezdíčka et al. 2020. PubMed ID: 33194915; Gianesello et al. 2021. PubMed ID: 34680992; Zhang et al. 2022. PubMed ID: 35919034; Mura-Escorche et al. 2023. PubMed ID: 38002082). This variant has not been reported in a large population database, indicating this variant is rare. Of note, different substitutions at the same codon have been reported in individuals with OCRL-related diseases (see for example, p.Arg318His in Ye et al. 2020. PubMed ID: 31674016 and Gianesello et al. 2021. PubMed ID: 34680992; p.Arg318Leu in Zhang et al. 2022. PubMed ID: 35919034 and Gianesello et al. 2021. PubMed ID: 34680992). The c.952C>T (p.Arg318Cys) variant is interpreted as pathogenic. -
Lowe syndrome Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.9
M;M
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-8.0
D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.92
Loss of MoRF binding (P = 0.004);Loss of MoRF binding (P = 0.004);
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.97
gMVP
0.93

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs137853263; hg19: chrX-128696373; COSMIC: COSV63980555; COSMIC: COSV63980555; API