ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.245G>A (p.Gly82Glu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000030.3(AGXT):c.245G>A (p.Gly82Glu)
Variation ID: 5643 Accession: VCV000005643.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 240869249 (GRCh38) [ NCBI UCSC ] 2: 241808666 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 9, 2014 Jul 15, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000030.3:c.245G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Gly82Glu missense NC_000002.12:g.240869249G>A NC_000002.11:g.241808666G>A NG_008005.1:g.5505G>A P21549:p.Gly82Glu - Protein change
- G82E
- Other names
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- Canonical SPDI
- NC_000002.12:240869248:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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AGXT | - | - |
GRCh38 GRCh37 |
905 | 1023 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000005997.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV001851685.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2023 | RCV003234894.8 |
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
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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
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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. |
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Pathogenic
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933841.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: AGXT c.245G>A (p.Gly82Glu) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. … (more)
Variant summary: AGXT c.245G>A (p.Gly82Glu) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.245G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Primary Hyperoxaluria Type 1 (e.g., Purdue_1992, Coulter-Mackie_2001). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in less than ~2% of normal catalytic activity in both patient derived samples and in an in vitro expression system (e.g., Purdue_1992, Cellini_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17696873, 11708860, 1349575). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria, type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047613.2
First in ClinVar: Oct 28, 2023 Last updated: Jul 15, 2024 |
Comment:
The observed missense variant c.245G>A (p.Gly82Glu) in gene has been reported in homozygous and compound heterozygous state individuals affected with Hyperoxaluria, primary (Milliner DS et … (more)
The observed missense variant c.245G>A (p.Gly82Glu) in gene has been reported in homozygous and compound heterozygous state individuals affected with Hyperoxaluria, primary (Milliner DS et al. 2022; Coulter-Mackie MB et al. 2001). Experimental studies have shown that this missense change affects AGXT function (Cellini B et al. 2007). The p.Gly82Glu variant has allele frequency 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid change p.Gly82Glu in AGXT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 82 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the kidney (present)
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Likely pathogenic
(Mar 07, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000485912.2
First in ClinVar: Jul 23, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002233889.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 82 of the AGXT protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 82 of the AGXT protein (p.Gly82Glu). This variant is present in population databases (rs121908522, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 1349575). This variant is also known as G367A. ClinVar contains an entry for this variant (Variation ID: 5643). 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) performed at Invitae indicates that this missense variant is expected to disrupt AGXT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 10960483, 17696873). This variant disrupts the p.Gly82 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15253729). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004194572.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Nov 17, 2000)
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no assertion criteria provided
Method: literature only
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HYPEROXALURIA, PRIMARY, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026179.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2014 |
Comment on evidence:
Purdue et al. (1992) found a G-to-A transition at nucleotide 367 of the AGXT cDNA, which was predicted to cause a glycine-to-glutamate substitution at residue … (more)
Purdue et al. (1992) found a G-to-A transition at nucleotide 367 of the AGXT cDNA, which was predicted to cause a glycine-to-glutamate substitution at residue 82 (G82Q) of the AGT protein. The mutation was located in exon 2 and led to the loss of an AvaI restriction site. The patient was homozygous. The same mutation was found in homozygous state in 1 related and 2 unrelated patients with type I primary hyperoxaluria (259900). One other phenotypically similar patient lacked the mutation, however. Lumb and Danpure (2000) noted that AGT carrying the G82E substitution does not affect the stability or mitochondria targeting of AGT, but eliminates its catalytic activity. Using recombinant proteins expressed in E. coli, they showed that AGT with this substitution did not bind the pyridoxal phosphate cofactor. (less)
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Pathogenic
(Nov 27, 2014)
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no assertion criteria provided
Method: in vitro
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Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV000239620.1
First in ClinVar: Jul 23, 2015 Last updated: Jul 23, 2015 |
Result:
In vitro activity: <2%
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Pathogenic
(Jan 17, 2019)
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no assertion criteria provided
Method: literature only
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Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106577.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000172451.3
First in ClinVar: Jul 24, 2014 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Primary Hyperoxaluria Type 1. | Adam MP | - | 2024 | PMID: 20301460 |
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 |
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 |
Mutation-based diagnostic testing for primary hyperoxaluria type 1: survey of results. | Coulter-Mackie MB | Clinical biochemistry | 2008 | PMID: 18282470 |
Human wild-type alanine:glyoxylate aminotransferase and its naturally occurring G82E variant: functional properties and physiological implications. | Cellini B | The Biochemical journal | 2007 | PMID: 17696873 |
Clinical implications of mutation analysis in primary hyperoxaluria type 1. | van Woerden CS | Kidney international | 2004 | PMID: 15253729 |
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 |
A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1. | Purdue PE | Genomics | 1992 | PMID: 1349575 |
http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf | - | - | - | - |
Text-mined citations for rs121908522 ...
HelpRecord last updated Sep 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.