ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.32C>T (p.Pro11Leu)
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.32C>T (p.Pro11Leu)
Variation ID: 5641 Accession: VCV000005641.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 240868897 (GRCh38) [ NCBI UCSC ] 2: 241808314 (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 20, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000030.3:c.32C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Pro11Leu missense NC_000002.12:g.240868897C>T NC_000002.11:g.241808314C>T NG_008005.1:g.5153C>T P21549:p.Pro11Leu - Protein change
- P11L
- Other names
- AGXT, PRO11LEU (rs34116584)
- Canonical SPDI
- NC_000002.12:240868896:C:T
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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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0.08087 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.07995
1000 Genomes Project 0.08087
Trans-Omics for Precision Medicine (TOPMed) 0.13754
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 | ||
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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
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
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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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Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Dec 23, 2023 | RCV000005995.26 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 24, 2023 | RCV000173049.19 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001513552.14 |
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. |
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000301569.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000429355.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Feb 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338182.3
First in ClinVar: Jun 22, 2020 Last updated: Mar 26, 2023 |
Comment:
Variant summary: AGXT c.32C>T (p.Pro11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: AGXT c.32C>T (p.Pro11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.15 in 246868 control chromosomes, predominantly at a frequency of 0.2 within the Non-Finnish European subpopulation in the gnomAD database, including 2253 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 101 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the variant, c.32C>T, has also been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1, together with two pathogenic variants (VanWoerden_2004, Lorenzo_2006, Kanoun_2013, Ahmed_2022). Clinical and functional data show that this variant leads to a synergistic effect with some common pathogenic variants (e.g. Gly170Arg and p.Ile244Thr), and the presence of this variant in the same chromosome (in cis) is required for their loss of function effect (Lumb_2000, Santana_2003, Monico_2007). Four ClinVar submitters (evaluation after 2014) cite this variant as benign (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Dec 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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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: SCV000239543.2
First in ClinVar: Jul 23, 2015 Last updated: Dec 30, 2023 |
Comment:
c.32C>T, although a common polymorphic variant with approximately 64% activity in vitro (PMID:10960483), it can influence the pathogenicity of some AGXT variants, for example see … (more)
c.32C>T, although a common polymorphic variant with approximately 64% activity in vitro (PMID:10960483), it can influence the pathogenicity of some AGXT variants, for example see c.836T>C (less)
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Benign
(Sep 24, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000224129.5
First in ClinVar: Jun 28, 2015 Last updated: Oct 02, 2016 |
Sex: mixed
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Likely benign
(Sep 29, 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: SCV002802776.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Feb 01, 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: SCV001721185.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024 |
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Benign
(Jan 25, 2013)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - ALANINE-GLYOXYLATE AMINOTRANSFERASE POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026177.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2017 |
Comment on evidence:
This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism. The pro11-to-leu substitution (P11L) is the primary polymorphism that defines the … (more)
This variant, formerly titled HYPEROXALURIA, PRIMARY, TYPE I, has been reclassified as a polymorphism. The pro11-to-leu substitution (P11L) is the primary polymorphism that defines the minor allele of AGXT that occurs with an allele frequency of 15 to 20% in European and North American populations and 50% of patients with primary hyperoxaluria type I (HP1; 259900). The absence of these polymorphisms defines the major allele. The P11L replacement creates a hidden N-terminal mitochondrial targeting sequence that can be unmasked by additional amino acid substitutions in cis, resulting in disease (summary by Fargue et al., 2013). Coulter-Mackie and Rumsby (2004) noted that the P11L substitution results from a 32C-T transition in exon 1 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: P11L, gly170-to-arg (G170R; 604285.0013), 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 the P11L variant is necessary and sufficient for the generation of a mitochondrial targeting sequence (MTS) in the AGT protein. The N-terminal 19 amino acids of AGT with this substitution were sufficient to direct mouse cytosolic dihydrofolate reductase to mitochondria. Although the P11L mutation creates an 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. Purdue et al. (1991) also studied the region of normal human AGT cDNA directly upstream of the coding region. They found that this sequence appears to correspond to an ancestral MTS deleted from the human coding region by a point mutation at the initiation codon. The reestablishment of this initiation codon produced an active MTS that was different from that observed in hyperoxaluria patients. The protein sorting defect found in approximately one-third of patients with primary hyperoxaluria type I is unique. The subcellular distribution of AGT is species-specific. The rat, for example, is one of a number of species in which AGT is a naturally occurring mitochondrial protein. In human AGT cDNA, the region homologous to that encoding the rat AGT MTS lies within the 5-prime untranslated region, being excluded from the open reading frame due to a coding difference (ATG in rat, ATA in human) at the rat-equivalent translation initiation site. The evolutionary loss of this ATG codon appears to explain the exclusive peroxisomal localization of human AGT; reestablishment of this codon could represent another mechanism for mitochondrial mistargeting of AGT in humans. Whereas humans, rabbits, and guinea pigs do not target AGT to the mitochondrion, rats, cats, and marmosets are among those species that do. 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. The P11L and G170R variants occur with other AGXT polymorphisms on the minor allele haplotype, which is population-dependent. The frequency of this minor allele haplotype is 10 to 20% in Caucasians, but only 2% in Japanese. In primary hyperoxaluria type I, the frequency is about 46% (Williams et al., 2009). Using recombinant epitope-tagged proteins expressed in E. coli, Lumb and Danpure (2000) determined the effects of the most common normal and disease-causing substitutions on the properties of AGT. Recombinant AGT expressed from the major allele was functionally similar to human liver AGT in binding alanine, glyoxylate, and pyridoxal phosphate in pH optima and in the ability to dimerize. However, recombinant AGT carrying the P11L and I340M variants (AGT(L11,M340)) associated with the minor allele had only 46 to 50% of the wildtype alanine:glyoxylate aminotransferase activity. The lower specific activity of the AGT(L11,M340) appeared to be entirely due to the presence of the P11L polymorphism rather than the I340M polymorphism, since the activity of AGT(L11) was about 25% of wildtype, and the activity of AGT(M340) was comparable or higher wildtype. Other mutations that segregate almost exclusively with the minor allele, G41R (604285.0005), F152I (604285.0006), and I244T (604285.0007), are associated with absence or near absence of immunoreactive AGT protein and catalytic activity. When AGT(R41) was expressed alone on the background of the major AGT allele, it showed 7% residual activity; however, the other substitutions showed between 44 and 59% residual activity and were predicted to be innocuous in the absence of P11L. The G170R substitution that segregates with the minor allele causes the mistargeting of AGT to mitochondria. (less)
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Benign
(Jan 10, 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: SCV001462981.1
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: SCV000172447.3
First in ClinVar: Jul 24, 2014 Last updated: Oct 01, 2022
Comment:
One of the variants that defines the haplotype "minor AGXT allele"
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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 |
Next-generation sequencing in identification of pathogenic variants in primary hyperoxaluria among 21 Egyptian families: Identification of two novel AGXT gene mutations. | Ahmed HA | Molecular genetics & genomic medicine | 2022 | PMID: 35661454 |
Pharmacogenetics of advanced lung cancer: Predictive value of functional genetic polymorphism AGXT Pro11Leu in clinical outcome? | Catarata MJ | Pulmonology | 2021 | PMID: 33408043 |
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: update and additional mutation analysis of the AGXT gene. | Williams EL | Human mutation | 2009 | PMID: 19479957 |
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 |
Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis. | Coulter-Mackie MB | Molecular genetics and metabolism | 2004 | PMID: 15464418 |
Clinical implications of mutation analysis in primary hyperoxaluria type 1. | van Woerden CS | Kidney international | 2004 | PMID: 15253729 |
Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. | Santana A | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12777626 |
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 |
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 | - | - | - | - |
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Text-mined citations for rs34116584 ...
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.