rs180177321
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_012203.2(GRHPR):c.864_865del(p.Val289AspfsTer22) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
GRHPR
NM_012203.2 frameshift, splice_region
NM_012203.2 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.85
Genes affected
GRHPR (HGNC:4570): (glyoxylate and hydroxypyruvate reductase) This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. The enzyme has widespread tissue expression and has a role in metabolism. Type II hyperoxaluria is caused by mutations in this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
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Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 9-37432134-CTG-C is Pathogenic according to our data. Variant chr9-37432134-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 162020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRHPR | NM_012203.2 | c.864_865del | p.Val289AspfsTer22 | frameshift_variant, splice_region_variant | 8/9 | ENST00000318158.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRHPR | ENST00000318158.11 | c.864_865del | p.Val289AspfsTer22 | frameshift_variant, splice_region_variant | 8/9 | 1 | NM_012203.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251436Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135904
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461644Hom.: 0 AF XY: 0.0000138 AC XY: 10AN XY: 727142
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary hyperoxaluria, type II Pathogenic:7
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic | Oct 27, 2023 | ACMG:PVS1 PM2 PM3 PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 14, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 10, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 31, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 25, 2017 | - - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2016 | Variant summary: The GRHPR c.864_865delTG (p.Val289Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent GRHPR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 3/121702 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). It was only found in East Asian population in which allele frequency was 0.033% (3/9124 chromosomes). This variant has been reported in five PH2 patients of East Asian origin including four patients who carried this variant in homozygous state (Takayama_2014). The authors recommend that this mutation, particularly in patients of East Asian origin, should be screened when PH2 is suspected. Multiple labs/reputable databases classify this variant as pathogenic. Taken together, this variant is classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change creates a premature translational stop signal (p.Val289Aspfs*22) in the GRHPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the GRHPR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 11728965, 24116921). This variant is also known as 862delTG. ClinVar contains an entry for this variant (Variation ID: 162020). This variant disrupts the p.Arg302 amino acid residue in GRHPR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635115, 24116921). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at