ClinVar Miner

Submissions for variant NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)

gnomAD frequency: 0.00001  dbSNP: rs180177314
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585941 SCV000699330 pathogenic Primary hyperoxaluria 2017-05-26 criteria provided, single submitter clinical testing 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.
Invitae RCV000802868 SCV000942714 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity RCV000186442 SCV002024912 pathogenic Primary hyperoxaluria, type II 2023-11-23 criteria provided, single submitter clinical testing
Suma Genomics RCV000186442 SCV002543796 pathogenic Primary hyperoxaluria, type II criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000186442 SCV002810400 pathogenic Primary hyperoxaluria, type II 2021-10-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000186442 SCV004191695 pathogenic Primary hyperoxaluria, type II 2023-10-19 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003927729 SCV004738173 pathogenic GRHPR-related condition 2023-12-11 criteria provided, single submitter clinical testing 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.
Clinical Biochemistry Laboratory, Health Services Laboratory RCV000186442 SCV000239796 pathogenic Primary hyperoxaluria, type II 2014-11-27 no assertion criteria provided in vitro
Counsyl RCV000186442 SCV001132215 likely pathogenic Primary hyperoxaluria, type II 2016-12-04 no assertion criteria provided clinical testing
Natera, Inc. RCV000186442 SCV002075677 pathogenic Primary hyperoxaluria, type II 2020-12-30 no assertion criteria provided clinical testing

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