rs121908529

chr2-240871433-G-Achr2-240871433-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM1 PP3_Strong PP5_Very_Strong

The NM_000030.3(AGXT):c.508G>A(p.Gly170Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,592,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G170G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 8.49

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000030.3 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2710435
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000030.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 2-240871433-G-A is Pathogenic according to our data. Variant chr2-240871433-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240871433-G-A is described in Lovd as [Pathogenic]. Variant chr2-240871433-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.508G>A	p.Gly170Arg	missense_variant	4/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.508G>A	p.Gly170Arg	missense_variant	4/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.528G>A		non_coding_transcript_exon_variant	4/5	2
AGXT	ENST00000476698.1	n.245G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000560 AC: 118 AN: 210718 Hom.: 1 AF XY: 0.000643 AC XY: 73 AN XY: 113538

Gnomad AFR exome AF: 0.0000779

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.000216

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.000166

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000564

GnomAD4 exome AF: 0.000985 AC: 1418 AN: 1440004 Hom.: 3 Cov.: 31 AF XY: 0.000972 AC XY: 694 AN XY: 714152

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000119

Gnomad4 ASJ exome AF: 0.000234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000727

Gnomad4 FIN exome AF: 0.000294

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000554

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74338

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000525

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000440 AC: 53

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:12 Other:1

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 28, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 19, 2018	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. -
Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jan 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 27, 2018	PS1, PS4, PP3, PP4, PP5 -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 02, 2023	PP3, PM3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -

AGXT-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2023

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. -

Primary hyperoxaluria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 15, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at G170 (P = 0.1531);
MVP		0.95
MPC		0.26
ClinPred		0.87	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908529; hg19: chr2-241810850;