rs180177314
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_012203.2(GRHPR):c.494G>A(p.Gly165Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000692 in 1,604,618 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_012203.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRHPR | NM_012203.2 | c.494G>A | p.Gly165Asp | missense_variant, splice_region_variant | Exon 6 of 9 | ENST00000318158.11 | NP_036335.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152260Hom.: 1 Cov.: 35
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251456Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135908
GnomAD4 exome AF: 0.0000682 AC: 99AN: 1452240Hom.: 1 Cov.: 31 AF XY: 0.0000940 AC XY: 68AN XY: 723226
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152378Hom.: 1 Cov.: 35 AF XY: 0.000148 AC XY: 11AN XY: 74530
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type II Pathogenic:8
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 04, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.494G>A(p.Gly165Asp) variant in GRHPR gene has been reported previously in homozygous state in individual(s) affected with Pediatric nephrolithiasis (NL) (Chatterjee et al., 2022). Experimental studies have shown that this missense change affects GRHPR function (Cregeen et al., 2003). This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Gly at position 165 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly165Asp in GRHPR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. The same variant in GRHPR [c.494G>A (p.Gly165Asp)] gene has been detected in heterozygous state in spouse. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 23, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 30, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2024 | Published functional studies demonstrate a damaging effect (PMID: 11030416, 14635115); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28660284, 11030416, 31685312, 14635115, 24116921, 14987413, 19296982, 16756993, 25629080, 35046417, 37881736, 36619171, 33752806, 38737343, 37803380) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 165 of the GRHPR protein (p.Gly165Asp). This variant is present in population databases (rs180177314, gnomAD 0.08%). This missense change has been observed in individual(s) with primary hyperoxaluria type 2 (PMID: 24116921, 25629080, 31685312). ClinVar contains an entry for this variant (Variation ID: 204235). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GRHPR function (PMID: 11030416, 14635115). For these reasons, this variant has been classified as Pathogenic. - |
GRHPR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The GRHPR c.494G>A variant is predicted to result in the amino acid substitution p.Gly165Asp. This variant has been reported in several unrelated individuals to be causative for primary hyperoxaluria type 2 (Webster et al 2000. PubMed ID: 11030416; Cregeen et al. 2003. PubMed ID: 14635115; Takayama et al. 2014. PubMed ID: 24116921; Garrelfs et al 2019. PubMed ID: 31685312). This variant is predicted to reside in the putative cofactor binding site and was also shown in functional studies to have significantly reduced glyoxylate reductase activity (Webster et al 2000. PubMed ID: 11030416). A recent study identified this variant in 5 individuals with pediatric nephrolithiasis and demonstrated significant differences (p < 0.05) in the enzyme activity between c.494G>A peripheral mononuclear cells (PMCs) and control PMCs (Chatterjee A et al 2022. PubMed ID: 36619171). In summary, the c.494G>A variant is categorized as pathogenic. - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2017 | Variant summary: The GRHPR c.494G>A (p.Gly165Asp) variant located in the putative cofactor binding site (Cregeen_2003) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. Functional studies support these predictions, which the variant significantly decreases glyoxylate reductase activity (Cregeen_2003 and Webster_200). This variant was found in 17/121252 control chromosomes, predominantly observed in the South Asian cohort at a frequency of 0.000969 (16/16508), which does not exceed the estimated maximal expected allele frequency of a pathogenic GRHPR variant (0.0014434). Multiple publications have cited the variant in affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at