Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000186451 | SCV000486244 | likely pathogenic | Primary hyperoxaluria, type II | 2016-04-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000806551 | SCV000946555 | pathogenic | not provided | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 7 of the GRHPR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRHPR are known to be pathogenic (PMID: 25644115). This variant is present in population databases (rs180177317, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with GRHPR-related conditions (PMID: 11030416, 28553045). ClinVar contains an entry for this variant (Variation ID: 204244). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000186451 | SCV001362966 | likely pathogenic | Primary hyperoxaluria, type II | 2023-12-15 | criteria provided, single submitter | clinical testing | Variant summary: GRHPR c.735-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Three predict the variant creates a new cryptic exonic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251356 control chromosomes (gnomAD). c.735-1G>A has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 2 (example, Webster_2000, Pinapala_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 14987413, 28553045, 11030416). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Revvity Omics, |
RCV000186451 | SCV002024913 | pathogenic | Primary hyperoxaluria, type II | 2023-06-21 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000186451 | SCV002811098 | likely pathogenic | Primary hyperoxaluria, type II | 2021-07-09 | criteria provided, single submitter | clinical testing | |
| Neuberg Centre For Genomic Medicine, |
RCV000186451 | SCV004048559 | likely pathogenic | Primary hyperoxaluria, type II | criteria provided, single submitter | clinical testing | The splice site c.735-1G>A variant has previously been reported in individuals affected with Primary Hyperoxaluria Type 2 (Webster_2000, Pinapala_2017). The variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001591% in gnomAD database. The nucleotide change in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D et al.), and loss-of-function variants in GRHPR are known to be pathogenic (Hopp K et al.). However since this variant is present in the penultimate intron functional studies will be required to prove protein truncation. For these reasons, this variant has been classified as Likely Pathogenic. | |
| Baylor Genetics | RCV000186451 | SCV004191719 | pathogenic | Primary hyperoxaluria, type II | 2024-02-19 | criteria provided, single submitter | clinical testing | |
| Clinical Biochemistry Laboratory, |
RCV000186451 | SCV000239806 | pathogenic | Primary hyperoxaluria, type II | 2014-11-27 | no assertion criteria provided | research |