Submissions for variant NM_000030.3(AGXT):c.508G>A (p.Gly170Arg)

gnomAD frequency: 0.00067  dbSNP: rs121908529

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000432954	SCV000331656	pathogenic	not provided	2015-10-09	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000432954	SCV000511372	likely pathogenic	not provided	2016-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000432954	SCV000617630	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Patients with the G170R variant have longer preservation of renal function with conservative treatment compared to other pathogenic variants and respond to pyridoxine treatment, a cofactor that reduces enzyme mistargeting (Monico et al., 2005; Harambat et al., 2010; Hopp et al., 2015); Functional studies demonstrate that G170R, when present in cis with the P11L AGXT variant, unmasks the cryptic mitochondrial targeting sequence encoded by P11L and results in the mistargeting of the AGT enzyme to the mitochondria instead of to the peroxisomes (Lumb et al., 2000; Montioli et al., 2014); 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: 1703535, 28660284, 34686543, 21103899, 34758253, 24797341, 23597595, 20713123, 22923379, 20564000, 18782763, 10960483, 23229545, 15840016, 11708860, 15802217, 22529745, 18985333, 20208150, 26161999, 26759051, 15356974, 27161247, 19479957, 31980526, 29431110, 28906061, 27915025, 27568336, 24205397, 25644115, 20016466, 30397603, 30655312, 24990153, 34426522, 33443292, 34008892, 34082749, 31589614, 11156702, 33726816, 31328266, 35964771)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589490	SCV000693979	pathogenic	Primary hyperoxaluria	2016-12-15	criteria provided, single submitter	clinical testing	Variant summary: The AGXT c.508G>A (p.Gly170Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 43/42102 control chromosomes at a frequency of 0.0010213, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). This variant has been reported as the most common AGXT mutation and found in multiple PH1 patients both as homozygotes and compound heterozygotes. Functional studies showed that G170R causes a folding defect leading to an erroneous targeting to mitochondria, where the enzyme cannot perform glyoxylate detoxification. The AGT mistargeting is due to the combined effects with the P11L polymorphism, which generates a functionally weak N-terminal mitochondrial targeting sequence, and the additional presence of the G170R replacement increases the functional efficiency of this polymorphic mitochondrial targeting sequence. Variant in isolation lead to decreased enzyme activity (~50% WT level, ranging from 40-90% from different reports). However, when variant of interest presents on the minor allele (co-occurrence of two polymorphic variants c.32C>T/P11L and c.1020A>G/I340M), the mutant protein showed non-detectable level of activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000032681	SCV000803508	likely pathogenic	Primary hyperoxaluria, type I	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Hyperoxaluria, primary, type I, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect on the activity of the minor allele (AGT-Mi). (PMID:19479957) (PMID:17495019) (PMID:10960483). PM2-Supporting =>PM2 downgraded in strength to Supporting (PMID:25644115) (PMID:25644115).
Fulgent Genetics, Fulgent Genetics	RCV000032681	SCV000894272	pathogenic	Primary hyperoxaluria, type I	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032681	SCV000914911	pathogenic	Primary hyperoxaluria, type I	2018-09-19	criteria provided, single submitter	clinical testing	The AGXT c.508G>A (p.Gly170Arg) variant is well described in the literature as one of the most common variants associated with primary hyperoxaluria type 1 (Coulter-Mackie et al. 2014). Across a subset of the literature, the p.Gly170Arg variant has been detected in at least 87 probands, including at least 71 in a homozygous state, at least 93 in a compound heterozygous state, and 30 in a heterozygous state with evidence suggesting these probands were actually compound heterozygous (Purdue et al. 1990; Rumsby et al. 2004; Harambat et al. 2010; Mandrile et al. 2014; Isivel et al 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.001892 in the European (non-Finnish) population of the Exome Aggregation Consortium. Liver biopsies from affected probands found that homozygotes for the p.Gly170Arg had a median AGT activity at 41% of normal, consistent with a less severe phenotype (Harambat et al. 2010). The effects of p.Gly170Arg may be exacerbated due the presence of p.Pro11Leu, also known as the minor allele, in cis which acts as a modifier allele (Williams et al. 2009). Based on the collective evidence, the p.Gly170Arg variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000032681	SCV000928384	pathogenic	Primary hyperoxaluria, type I	2018-07-27	criteria provided, single submitter	clinical testing	PS1, PS4, PP3, PP4, PP5
Invitae	RCV000432954	SCV000944322	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 170 of the AGXT protein (p.Gly170Arg). This variant is present in population databases (rs121908529, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 1703535, 11708860, 15356974, 15840016, 18985333, 20016466, 24988064). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 630G>A. ClinVar contains an entry for this variant (Variation ID: 40166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 10960483, 17110443, 23229545). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000032681	SCV000966875	pathogenic	Primary hyperoxaluria, type I	2018-04-10	criteria provided, single submitter	clinical testing	The p.Gly170Arg variant in AGXT has been reported in >200 homozygous or compound heterozygous individuals with clinical features of primary hyperoxaluria (PH), representing roughly 25-40% of all alleles in PH patient registries (Harambat 20 10, Mandrile 2014, Hopp 2015). This variant has been identified in 0.1% (111/105 692) of European chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs121908529). In vitro functional studies provi de some evidence that the p.Gly170Arg variant may impact protein function by mis localization and decreased catalytic activity (Fargue 2013); however, these type s of assays may not accurately represent biological function. In summary, this v ariant meets criteria to be classified as pathogenic for primary hyperoxaluriai n an autosomal recessive manner based upon extreme enrichment in PH patients, f unctional evidence, and predicted impact on protein. ACMG/AMP Criteria applied: PM3_VeryStrong; PS4; PS3_Supporting
Baylor Genetics	RCV000032681	SCV001162943	pathogenic	Primary hyperoxaluria, type I		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000032681	SCV001193829	pathogenic	Primary hyperoxaluria, type I	2019-12-20	criteria provided, single submitter	clinical testing	NM_000030.2(AGXT):c.508G>A(G170R) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 10960483, 15840016, 22529745, 18782763, 24205397, and 24988064. Classification of NM_000030.2(AGXT):c.508G>A(G170R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000432954	SCV001246473	pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000432954	SCV001715799	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	PP3, PM3, PS3, PS4
Revvity Omics, Revvity	RCV000032681	SCV002023769	pathogenic	Primary hyperoxaluria, type I	2023-09-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407388	SCV004115838	pathogenic	AGXT-related condition	2023-07-21	criteria provided, single submitter	clinical testing	The AGXT c.508G>A variant is predicted to result in the amino acid substitution p.Gly170Arg. This variant is one of the most common AGXT pathogenic variants and has been reported in the compound heterozygous and homozygous state in many individuals with primary hyperoxaluria (Purdue et al. 1990. PubMed ID: 1703535; Rumsby et al. 2004. PubMed ID: 15327387; Harambat et al. 2009. PubMed ID: 20016466; Williams et al. 2009. PubMed ID: 19479957). Functional studies indicate this variant results in impaired enzymatic activity and mislocalization of the AGT protein (Purdue et al. 1990. PubMed ID: 1703535; Lumb et al. 2000. PubMed ID: 10960483; Coulter-Mackie et al. 2005. PubMed ID: 15802217). Homozygous individuals are found to have a AGT activity of 41% of normal, which is consistent with a less severe phenotype in these individuals (Harambat et al. 2009. PubMed ID: 20016466). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241810850-G-A). This variant is interpreted as pathogenic.
OMIM	RCV000032681	SCV000056444	pathogenic	Primary hyperoxaluria, type I	2006-11-28	no assertion criteria provided	literature only
GeneReviews	RCV000032681	SCV000172454	not provided	Primary hyperoxaluria, type I		no assertion provided	literature only
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000032681	SCV000239650	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	in vitro
Genomics England Pilot Project, Genomics England	RCV000032681	SCV001760080	pathogenic	Primary hyperoxaluria, type I		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000032681	SCV002106576	pathogenic	Primary hyperoxaluria, type I	2019-01-17	no assertion criteria provided	literature only