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
Consequence
ENST00000371113.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OCRL | NM_000276.4 | c.952C>T | p.Arg318Cys | missense_variant | 11/24 | ENST00000371113.9 | NP_000267.2 | |
OCRL | NM_001318784.2 | c.955C>T | p.Arg319Cys | missense_variant | 11/24 | NP_001305713.1 | ||
OCRL | NM_001587.4 | c.952C>T | p.Arg318Cys | missense_variant | 11/23 | NP_001578.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OCRL | ENST00000371113.9 | c.952C>T | p.Arg318Cys | missense_variant | 11/24 | 1 | NM_000276.4 | ENSP00000360154 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Dent disease type 2 Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 06, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The 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 submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2017 | - - |
OCRL-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 25, 2024 | The 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 provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at