This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). 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 individual(s) with primary hyperoxaluria type 1 (PMID: 15849466, 17460142, 17495019, 23430879, 25629080, 30541997). 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: 204103). 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: 18782763, 22018727, 22923379). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.473C>T (p.Ser158Leu)
Germline
Classification
Help
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.
(8)
Help
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
8
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.473C>T (p.Ser158Leu)
Variation ID: 204103 Accession: VCV000204103.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240871398 (GRCh38) [ NCBI UCSC ] 2: 241810815 (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 Jul 21, 2015 Sep 29, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000030.3:c.473C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Ser158Leu missense NC_000002.12:g.240871398C>T NC_000002.11:g.241810815C>T NG_008005.1:g.7654C>T P21549:p.Ser158Leu - Protein change
- S158L
- Other names
- -
- Canonical SPDI
- NC_000002.12:240871397:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000186309.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2024 | RCV001233993.16 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
GenePathDx, GenePath diagnostics
Accession: SCV000616342.2
First in ClinVar: Jul 21, 2015 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Sex: male
|
|
|
Likely pathogenic
(Jan 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485635.2
First in ClinVar: Jul 21, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001406618.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). 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 individual(s) with primary hyperoxaluria type 1 (PMID: 15849466, 17460142, 17495019, 23430879, 25629080, 30541997). 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: 204103). 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: 18782763, 22018727, 22923379). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004196514.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809537.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Feb 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325406.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30655312, 22923379, 15849466, 18782763, 22018727, 30541997) (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: SCV000239644.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
In vitro activity: <1% on major and minor alleles. Predominantly Asian ethnicity.
|
|
|
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: SCV002106578.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
|
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30655312, 22923379, 15849466, 18782763, 22018727, 30541997)
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:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 158 of the AGXT protein (p.Ser158Leu). 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 individual(s) with primary hyperoxaluria type 1 (PMID: 15849466, 17460142, 17495019, 23430879, 25629080, 30541997). 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: 204103). 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: 18782763, 22018727, 22923379). For these reasons, this variant has been classified as Pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30655312, 22923379, 15849466, 18782763, 22018727, 30541997)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| A Putative Mutation Hotspot of the AGXT Gene Associated with Primary Hyperoxaluria Type 1 in the Chinese Population. | Li X | The Tohoku journal of experimental medicine | 2018 | PMID: 30541997 |
| 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 |
| Hyperoxaluria and rapid development of renal failure following a combined liver and kidney transplantation: emphasis on sequential transplantation. | Alkhunaizi AM | JIMD reports | 2012 | PMID: 23430879 |
| Rapid profiling of disease alleles using a tunable reporter of protein misfolding. | Pittman AM | Genetics | 2012 | PMID: 22923379 |
| Biochemical analyses are instrumental in identifying the impact of mutations on holo and/or apo-forms and on the region(s) of alanine:glyoxylate aminotransferase variants associated with primary hyperoxaluria type I. | Oppici E | Molecular genetics and metabolism | 2012 | PMID: 22018727 |
| 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 |
| Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. | Monico CG | American journal of nephrology | 2005 | PMID: 15849466 |
| http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf | - | - | - | - |
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Text-mined citations for rs180177225 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.