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

gnomAD frequency: 0.00001  dbSNP: rs180177314

Total submissions: 12

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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000186442	SCV004191695	pathogenic	Primary hyperoxaluria, type II	2024-03-19	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000186442	SCV005329576	pathogenic	Primary hyperoxaluria, type II		criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000802868	SCV005874617	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	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)
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
PreventionGenetics, part of Exact Sciences	RCV003927729	SCV004738173	pathogenic	GRHPR-related disorder	2023-12-11	no assertion criteria provided	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.