VCV000040166.63 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(22)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 40166 Accession: VCV000040166.63

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240871433 (GRCh38) [ NCBI UCSC ] 2: 241810850 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Oct 20, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000030.3:c.508G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000021.1:p.Gly170Arg	missense
NC_000002.12:g.240871433G>A
NC_000002.11:g.241810850G>A
NG_008005.1:g.7689G>A
	P21549:p.Gly170Arg

... more HGVS ... less HGVS

Protein change

G170R

Other names

NM_000030.2(AGXT):c.508G>A(p.Gly170Arg)

Canonical SPDI

NC_000002.12:240871432:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00053

The Genome Aggregation Database (gnomAD), exomes 0.00056

The Genome Aggregation Database (gnomAD) 0.00067

Exome Aggregation Consortium (ExAC) 0.00102

Links

ClinGen: CA343785 UniProtKB: P21549#VAR_000590 OMIM: 604285.0013 dbSNP: rs121908529 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AGXT		-	-	GRCh38 GRCh37	914	1034

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary hyperoxaluria, type I	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000032681.40
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000432954.49
Primary hyperoxaluria	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2016	RCV000589490.9
AGXT-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 5, 2024	RCV003407388.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000944322.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 1703535‚ 11708860‚ 15356974‚ 15840016‚ 18985333‚ 20016466‚ 24988064‚ 10960483‚ 17110443‚ 23229545 Comment: 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). … (more) 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. (less)
Likely pathogenic (Sep 08, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511372.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Pathogenic (Dec 15, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Primary hyperoxaluria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000693979.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (6) PubMed: 22529745‚ 24990153‚ 15802217‚ 20713123‚ 1703535‚ 10960483 Comment: 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. … (more) 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. (less)
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803508.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (4) PubMed: 19479957‚ 17495019‚ 10960483‚ 25644115 Comment: 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 => … (more) 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). (less)
Pathogenic (Oct 09, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331656.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 15802217‚ 20713123‚ 22529745 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGXT Number of individuals with the variant: 4 Sex: mixed
Pathogenic (Jul 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV000928384.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Comment: PS1, PS4, PP3, PP4, PP5
Pathogenic (Apr 10, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Primary hyperoxaluria, type I (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966875.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (5) PubMed: 23229545‚ 16208537‚ 25644115‚ 20016466‚ 24988064 Comment: 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% … (more) 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 (less) Number of individuals with the variant: 1
Pathogenic (Dec 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617630.3 First in ClinVar: Dec 19, 2017 Last updated: Jan 15, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162943.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Mar 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246473.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894272.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914911.1 First in ClinVar: May 24, 2019 Last updated: May 24, 2019	Publications: PubMed (7) PubMed: 1703535‚ 20301460‚ 20016466‚ 24988064‚ 27915025‚ 19479957‚ 15327387 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193829.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (6) PubMed: 10960483‚ 15840016‚ 22529745‚ 18782763‚ 24205397‚ 24988064 Comment: 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, … (more) 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. (less)
Pathogenic (Mar 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715799.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (12) PubMed: 10400689‚ 10960483‚ 12737622‚ 15802217‚ 15840016‚ 17460142‚ 17495019‚ 20208150‚ 20713123‚ 23229545‚ 24990153‚ 25644115 Comment: PP3, PM3, PS3, PS4 Number of individuals with the variant: 4
Pathogenic (Sep 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023769.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086818.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 20016466‚ 20301460‚ 35695965 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type 1 (MIM#259900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability has been reported for affected relatives carrying the same pathogenic variant (PMIDs: 20301460, 35695965). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (134 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aminotransferase class-V domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and is well reported as both homozygous and compound heterozygous in individuals with primary hyperoxaluria (PMID: 20016466). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Nov 28, 2006)	no assertion criteria provided Method: literature only	HYPEROXALURIA, PRIMARY, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056444.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2015	Publications: PubMed (6) PubMed: 15464418‚ 1703535‚ 1961759‚ 17110443‚ 10453743‚ 10960483 Comment on evidence: Coulter-Mackie and Rumsby (2004) noted that the gly170-to-arg (G170R) mutation results from a 508G-A (with position 1 being the first coding nucleotide) transition in exon … (more) Coulter-Mackie and Rumsby (2004) noted that the gly170-to-arg (G170R) mutation results from a 508G-A (with position 1 being the first coding nucleotide) transition in exon 4 of AGXT. Purdue et al. (1990) found that approximately one-third of patients with type I primary hyperoxaluria have an allele carrying 3 point mutations, each of which specifies a single amino acid substitution: pro11-to-leu (P11L; 604285.0002), G170R, and ile340-to-met (I340M; 604285.0014). A minority of such patients are homozygous for this allele; most appear to be heterozygous, i.e., compound heterozygotes. The G170R substitution was not found in controls; however, the other 2 mutations cosegregated in the normal population at an allelic frequency of 5 to 10%. Studies suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import. Purdue et al. (1991) showed that although the P11L mutation creates a mitochondrial targeting sequence (MTS), the G170R mutation appeared to be necessary for redirection of AGT to the mitochondria, presumably by interfering with the mechanism of targeting to peroxisomes. Salido et al. (2006) showed that transgenic mice predominantly expressed wildtype human AGT1 in hepatocellular peroxisomes, whereas AGT1 with the G170R mutation localized to mitochondria. In a study of 15 unrelated Italian patients with type I primary hyperoxaluria, Pirulli et al. (1999) found that the most frequent AGXT allele carried the G170R mutation, with a prevalence of 30%. The mutation results from a 630G-A transition. The mutation was found on the background of the minor allele. Lumb and Danpure (2000) found that the G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. (less)
Pathogenic (Jan 17, 2019)	no assertion criteria provided Method: literature only	Primary hyperoxaluria, type I Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106576.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 30655312
Pathogenic (Mar 05, 2024)	no assertion criteria provided Method: clinical testing	AGXT-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115838.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 27, 2014)	no assertion criteria provided Method: in vitro	Primary hyperoxaluria, type I Affected status: yes Allele origin: germline	Clinical Biochemistry Laboratory, Health Services Laboratory Accession: SCV000239650.1 First in ClinVar: Jul 23, 2015 Last updated: Jul 23, 2015	Publications: PubMed (2) PubMed: 1703535‚ 10960483 Other databases http://www.uclh.nhs.uk/OurServic… http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf Result: In vitro activity: 40% on minor allele; 68% on major.
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Primary hyperoxaluria, type I Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760080.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
not provided (-)	no classification provided Method: literature only	Primary hyperoxaluria, type I Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000172454.3 First in ClinVar: Jul 24, 2014 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1283 BookShelf: NBK1283
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Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type 1 (MIM#259900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability has been reported for affected relatives carrying the same pathogenic variant (PMIDs: 20301460, 35695965). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (134 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aminotransferase class-V domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and is well reported as both homozygous and compound heterozygous in individuals with primary hyperoxaluria (PMID: 20016466). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

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. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Primary Hyperoxaluria Type 1.	Adam MP	-	2024	PMID: 20301460
Genetic assessment in primary hyperoxaluria: why it matters.	Mandrile G	Pediatric nephrology (Berlin, Germany)	2023	PMID: 35695965
Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.	Mann N	Journal of the American Society of Nephrology : JASN	2019	PMID: 30655312
Molecular analysis of the AGXT gene in patients suspected with hyperoxaluria type 1 and three novel mutations from Turkey.	Isiyel E	Molecular genetics and metabolism	2016	PMID: 27915025
Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.	Hopp K	Journal of the American Society of Nephrology : JASN	2015	PMID: 25644115
S81L and G170R mutations causing Primary Hyperoxaluria type I in homozygosis and heterozygosis: an example of positive interallelic complementation.	Montioli R	Human molecular genetics	2014	PMID: 24990153
Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type.	Mandrile G	Kidney international	2014	PMID: 24988064
The role of protein denaturation energetics and molecular chaperones in the aggregation and mistargeting of mutants causing primary hyperoxaluria type I.	Mesa-Torres N	PloS one	2013	PMID: 24205397
Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.	Fargue S	The Journal of biological chemistry	2013	PMID: 23229545
Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.	Fodor K	PLoS biology	2012	PMID: 22529745
Human liver peroxisomal alanine:glyoxylate aminotransferase: Different stability under chemical stress of the major allele, the minor allele, and its pathogenic G170R variant.	Cellini B	Biochimie	2010	PMID: 20713123
Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting.	Djordjevic S	Acta crystallographica. Section F, Structural biology and crystallization communications	2010	PMID: 20208150
Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome.	Harambat J	Kidney international	2010	PMID: 20016466
Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene.	Williams EL	Human mutation	2009	PMID: 19479957
Primary hyperoxaluria: report of an Italian family with clear sex conditioned penetrance.	Mandrile G	Urological research	2008	PMID: 18985333
In vivo and in vitro examination of stability of primary hyperoxaluria-associated human alanine:glyoxylate aminotransferase.	Hopper ED	The Journal of biological chemistry	2008	PMID: 18782763
Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1.	Williams E	Clinical chemistry	2007	PMID: 17495019
Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis.	Monico CG	Journal of the American Society of Nephrology : JASN	2007	PMID: 17460142
Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer.	Salido EC	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 17110443
An overview of the role of genotyping in the diagnosis of the primary hyperoxalurias.	Rumsby G	Urological research	2005	PMID: 16208537
Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele.	Monico CG	Kidney international	2005	PMID: 15840016
Overexpression of human alanine:glyoxylate aminotransferase in Escherichia coli: renaturation from guanidine-HCl and affinity for pyridoxal phosphate co-factor.	Coulter-Mackie MB	Protein expression and purification	2005	PMID: 15802217
Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis.	Coulter-Mackie MB	Molecular genetics and metabolism	2004	PMID: 15464418
Late-onset primary hyperoxaluria triggered by hypothyroidism and presenting as rapidly progressive renal failure--description of a new mutation.	Tintillier M	Clinical nephrology	2004	PMID: 15356974
Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias.	Rumsby G	Kidney international	2004	PMID: 15327387
Correction of an enzyme trafficking defect in hereditary kidney stone disease in vitro.	Lumb MJ	The Biochemical journal	2003	PMID: 12737622
Three novel deletions in the alanine:glyoxylate aminotransferase gene of three patients with type 1 hyperoxaluria.	Coulter-Mackie MB	Molecular genetics and metabolism	2001	PMID: 11708860
Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.	Lumb MJ	The Journal of biological chemistry	2000	PMID: 10960483
Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene.	Pirulli D	Human genetics	1999	PMID: 10453743
Effect of N-terminal alpha-helix formation on the dimerization and intracellular targeting of alanine:glyoxylate aminotransferase.	Lumb MJ	The Journal of biological chemistry	1999	PMID: 10400689
Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation.	Purdue PE	Proceedings of the National Academy of Sciences of the United States of America	1991	PMID: 1961759
Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.	Purdue PE	The Journal of cell biology	1990	PMID: 1703535
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGXT	-	-	-	-
http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf	-	-	-	-
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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908529 ...