Submissions for variant NM_000276.4(OCRL):c.2530C>T (p.Arg844Ter)

dbSNP: rs387906484

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000011604	SCV000753971	pathogenic	Lowe syndrome	2023-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 10857). This variant is also known as c.2746C>T. This premature translational stop signal has been observed in individuals with Lowe syndrome (PMID: 8504307). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg844*) in the OCRL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OCRL are known to be pathogenic (PMID: 19390221, 21031565, 22381590).
GeneDx	RCV001588808	SCV001823431	pathogenic	not provided	2019-05-31	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 58 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21031565, 25525159, 8504307)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011604	SCV002768787	pathogenic	Lowe syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Lowe syndrome (MIM#309000) and Dent disease 2 (MIM#300555). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 – Other truncating variants downstream to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic (ClinVar, PMID: 21031565). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and observed in patients with Lowe syndrome (ClinVar, PMID: 21031565). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001940). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002496327	SCV002808936	pathogenic	Dent disease type 2; Lowe syndrome	2021-09-28	criteria provided, single submitter	clinical testing
OMIM	RCV000011604	SCV000031836	pathogenic	Lowe syndrome	1993-04-01	no assertion criteria provided	literature only