ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.481G>A (p.Gly161Ser)
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.481G>A (p.Gly161Ser)
Variation ID: 204105 Accession: VCV000204105.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 240871406 (GRCh38) [ NCBI UCSC ] 2: 241810823 (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 Jul 21, 2015 Feb 14, 2024 Oct 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000030.3:c.481G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Gly161Ser missense NC_000002.12:g.240871406G>A NC_000002.11:g.241810823G>A NG_008005.1:g.7662G>A P21549:p.Gly161Ser - Protein change
- G161S
- Other names
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- Canonical SPDI
- NC_000002.12:240871405: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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00006
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 |
892 | 1004 |
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
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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 (3) |
criteria provided, single submitter
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Mar 22, 2023 | RCV000186311.12 | |
Likely pathogenic (1) |
no assertion criteria provided
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Sep 8, 2017 | RCV000662317.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2023 | RCV001069631.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV003226241.8 |
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
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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
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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
(Mar 14, 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: SCV003922510.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: AGXT c.481G>A (p.Gly161Ser) 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.481G>A (p.Gly161Ser) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Three variants, namely p.Gly161Arg/Ser/Cys affecting this residue have been reported among PH1 patients: p.G161R on the major allele and p.G161S and p.G161C on the minor allele. These mutations are predicted to interfere with AGT folding promoting protein aggregation (reviewed in Mandrile_2023). 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 1.8e-05 in 226372 control chromosomes. c.481G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Primary Hyperoxaluria Type 1 (example, Daga_2018, Williams_2015). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 22, 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: SCV004192750.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 12, 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: SCV001234810.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the AGXT protein (p.Gly161Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the AGXT protein (p.Gly161Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 17460142, 25629080, 28893421). ClinVar contains an entry for this variant (Variation ID: 204105). 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 not expected to disrupt AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 24055001). This variant disrupts the p.Gly161 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25629080; Invitae). 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
(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: SCV000239647.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
In vitro activity: <1% on minor allele;15% on major. Reduce expression and half-life of AGT; aggregation. Decreased stability on major and minor allele.
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Likely pathogenic
(Sep 08, 2017)
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no assertion criteria provided
Method: literature only
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Nephrolithiasis
Nephrocalcinosis
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784649.1
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Pathogenic
(Aug 12, 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: SCV002076461.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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Genetic assessment in primary hyperoxaluria: why it matters. | Mandrile G | Pediatric nephrology (Berlin, Germany) | 2023 | PMID: 35695965 |
Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. | Daga A | Kidney international | 2018 | PMID: 28893421 |
Performance evaluation of Sanger sequencing for the diagnosis of primary hyperoxaluria and comparison with targeted next generation sequencing. | Williams EL | Molecular genetics & genomic medicine | 2015 | PMID: 25629080 |
Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria. | Lage MD | PloS one | 2014 | PMID: 24718375 |
Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. | Oppici E | Biochimica et biophysica acta | 2013 | PMID: 24055001 |
Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. | Williams EL | Human mutation | 2009 | PMID: 19479957 |
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 |
http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf | - | - | - | - |
Text-mined citations for rs180177227 ...
HelpRecord last updated Apr 15, 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.