ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.822G>C (p.Glu274Asp)
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.
Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000030.3(AGXT):c.822G>C (p.Glu274Asp)
Variation ID: 204129 Accession: VCV000204129.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240875980 (GRCh38) [ NCBI UCSC ] 2: 241815397 (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 Dec 9, 2023 Oct 27, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000030.3:c.822G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Glu274Asp missense NC_000002.12:g.240875980G>C NC_000002.11:g.241815397G>C NG_008005.1:g.12236G>C - Protein change
- E274D
- Other names
- -
- Canonical SPDI
- NC_000002.12:240875979:G:C
-
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.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
906 | 1024 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Oct 27, 2023 | RCV000186335.20 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 19, 2022 | RCV001852426.13 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Oct 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914912.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The AGXT c.822G>C (p.Glu274Asp) variant is a missense variant has been reported in a homozygous state in at least one individual with primary hyperoxaluria (Williams … (more)
The AGXT c.822G>C (p.Glu274Asp) variant is a missense variant has been reported in a homozygous state in at least one individual with primary hyperoxaluria (Williams et al. 2009; Williams et al. 2015). The p.Glu274Asp variant is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Database. Functional studies in yeast and bacteria revealed that the p.Glu274Asp variant in the background of a well-known AGXT variant protein, had significantly reduced activity when compared to the wild type expressed in the same background (Lage et al. 2014). The evidence for this variant is limited. The p.Glu274Asp variant is classified as unknown significance but suspicious for pathogenicity for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Uncertain significance
(Oct 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060081.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000030.2(AGXT):c.822G>C(E274D) is a missense variant classified as a variant of uncertain significance in the context of primary hyperoxaluria type 1. E274D has been observed in … (more)
NM_000030.2(AGXT):c.822G>C(E274D) is a missense variant classified as a variant of uncertain significance in the context of primary hyperoxaluria type 1. E274D has been observed in cases with relevant disease (PMID: 24988064). Functional assessments of this variant are available in the literature (PMID: 22923379, 24718375). E274D has been observed in population frequency databases (gnomAD: EAS 0.03%). In summary, there is insufficient evidence to classify NM_000030.2(AGXT):c.822G>C(E274D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
Uncertain significance
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002815658.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Feb 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002299289.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 274 of the AGXT … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 274 of the AGXT protein (p.Glu274Asp). This variant is present in population databases (rs146525143, gnomAD 0.03%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 19479957, 25629080). ClinVar contains an entry for this variant (Variation ID: 204129). 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. Experimental studies have shown that this missense change affects AGXT function (PMID: 24718375). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic
Accession: SCV004171790.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
ACMG:PS3 PS5 PM2 PP1 PP3 PP4
|
|
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: SCV000239681.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
In vitro activity: <3%. Normal activity on major.
|
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 |
---|---|---|---|---|
Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. | Hopp K | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25644115 |
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 |
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 |
Allele-specific characterization of alanine: glyoxylate aminotransferase variants associated with primary hyperoxaluria. | Lage MD | PloS one | 2014 | PMID: 24718375 |
Rapid profiling of disease alleles using a tunable reporter of protein misfolding. | Pittman AM | Genetics | 2012 | PMID: 22923379 |
Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. | Williams EL | Human mutation | 2009 | PMID: 19479957 |
http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf | - | - | - | - |
Text-mined citations for rs146525143 ...
HelpRecord last updated Sep 29, 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.