ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.454T>A (p.Phe152Ile)
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.454T>A (p.Phe152Ile)
Variation ID: 5645 Accession: VCV000005645.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 240871379 (GRCh38) [ NCBI UCSC ] 2: 241810796 (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 Mar 24, 2015 Feb 14, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000030.3:c.454T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Phe152Ile missense NC_000002.12:g.240871379T>A NC_000002.11:g.241810796T>A NG_008005.1:g.7635T>A P21549:p.Phe152Ile - Protein change
- F152I
- Other names
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- Canonical SPDI
- NC_000002.12:240871378:T: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.
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00016
Exome Aggregation Consortium (ExAC) 0.00017
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 |
891 | 1005 |
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 (8) |
criteria provided, multiple submitters, no conflicts
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Sep 18, 2023 | RCV000005999.19 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000727639.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 2, 2018 | RCV000779687.9 |
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
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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. |
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Pathogenic
(Jun 14, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854923.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jul 02, 2018)
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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: SCV000916431.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: AGXT c.454T>A (p.Phe152Ile) 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.454T>A (p.Phe152Ile) 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 7.6e-05 in 248758 control chromosomes (gnomAD). The variant, c.454T>A, has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1 (van der Hoeven_2012, Monico_2007). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 11, 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: SCV000486336.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 14, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813829.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 18, 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: SCV004194638.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 26, 2024)
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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: SCV001232267.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 152 of the AGXT protein (p.Phe152Ile). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 152 of the AGXT protein (p.Phe152Ile). This variant is present in population databases (rs121908524, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 8101040, 11708860, 25363903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5645). 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). For these reasons, this variant has been classified as Pathogenic. (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: SCV000239641.1
First in ClinVar: Jul 23, 2015 Last updated: Jul 23, 2015 |
Result:
In vitro activity: <2%
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Pathogenic
(Jan 25, 2013)
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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: SCV000026181.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 05, 2015 |
Comment on evidence:
See 604285.0005 and Danpure et al. (1993). AGT exists as 2 polymorphic variants, a major allele (AGT-Ma) and a minor allele (AGT-Mi) (see 604285.0002), which … (more)
See 604285.0005 and Danpure et al. (1993). AGT exists as 2 polymorphic variants, a major allele (AGT-Ma) and a minor allele (AGT-Mi) (see 604285.0002), which shows lower AGT activity compared with AGT-Ma. AGT-Mi also causes PH1 only when combined with specific mutations, including F152I. Cellini et al. (2009) showed that the F152I substitution does not affect the transaminase activity of AGT-Mi, but plays a role in stabilizing the aminated cofactor, pyridoxamine 5-prime-phosphate (PMP) produced during the L-alanine half-transamination reaction. The F152I substitution in both AGT-Mi and AGT-Ma caused the premature release of PMP, resulting in the formation of the apoenzyme in both isoforms. In the context of AGT-Mi, however, F152I additionally causes destabilization of the enzyme at physiologic temperatures, with concomitant protein aggregation and loss of enzyme activity. Fargue et al. (2013) found that the F152I mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. (less)
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Pathogenic
(May 13, 2014)
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no assertion criteria provided
Method: clinical testing
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Primary hyperoxaluria, type I
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV000223918.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Primary hyperoxaluria type I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456047.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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: SCV000172452.3
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 | - | 2022 | PMID: 20301460 |
Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria. | Berini SE | Muscle & nerve | 2015 | PMID: 25363903 |
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 |
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 |
Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. | van der Hoeven SM | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2012 | PMID: 22844106 |
Molecular Insight into the Synergism between the Minor Allele of Human Liver Peroxisomal Alanine:Glyoxylate Aminotransferase and the F152I Mutation. | Cellini B | The Journal of biological chemistry | 2009 | PMID: 19155213 |
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 |
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 |
Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease. | Danpure CJ | BioEssays : news and reviews in molecular, cellular and developmental biology | 1997 | PMID: 9136629 |
Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation. | Danpure CJ | American journal of human genetics | 1993 | PMID: 8101040 |
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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Text-mined citations for rs121908524 ...
HelpRecord last updated Mar 23, 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.