Variant summary: AGXT c.32C>G (p.Pro11Arg) results in a non-conservative amino acid change in 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 0.00016 in 246986 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00016 vs 0.0024), allowing no conclusion about variant significance. c.32C>G has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009, Tammachote_2012, Krishnamurthy_2017, Zhao_2020, Lin_2021, Saha_2023). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact on protein function and results in reduced the enzymatic activity (Williams_2009, Tammachote_2012). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.32C>G (p.Pro11Arg)
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.
(14)
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
14
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.32C>G (p.Pro11Arg)
Variation ID: 204069 Accession: VCV000204069.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240868897 (GRCh38) [ NCBI UCSC ] 2: 241808314 (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 Oct 20, 2024 Sep 18, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000030.3:c.32C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Pro11Arg missense NC_000002.12:g.240868897C>G NC_000002.11:g.241808314C>G NG_008005.1:g.5153C>G - Protein change
- P11R
- Other names
- -
- Canonical SPDI
- NC_000002.12:240868896:C:G
-
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.
-
0.08087 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00016
- 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 (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000186275.25 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2023 | RCV001553704.10 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 18, 2024 | RCV001857587.20 |
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
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001774677.2
First in ClinVar: Aug 07, 2021 Last updated: Feb 04, 2024 |
Comment:
Variant summary: AGXT c.32C>G (p.Pro11Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: AGXT c.32C>G (p.Pro11Arg) results in a non-conservative amino acid change in 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 0.00016 in 246986 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00016 vs 0.0024), allowing no conclusion about variant significance. c.32C>G has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009, Tammachote_2012, Krishnamurthy_2017, Zhao_2020, Lin_2021, Saha_2023). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact on protein function and results in reduced the enzymatic activity (Williams_2009, Tammachote_2012). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001162942.2
First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Feb 01, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
Arcensus
Accession: SCV002564579.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Likely pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002783742.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003809059.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002232412.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the AGXT protein (p.Pro11Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the AGXT protein (p.Pro11Arg). This variant is present in population databases (rs34116584, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 22821680, 32556641). 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: 204069). 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 95%. Experimental studies have shown that this missense change affects AGXT function (PMID: 22821680). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Primary hyperoxaluria, type I
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051821.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002513151.4
First in ClinVar: May 21, 2022 Last updated: Oct 13, 2024 |
Comment:
Published functional studies demonstrate showed that p.(P11R) reduced the enzymatic activity to about 31% of the wild-type (PMID: 22821680); In silico analysis supports that this … (more)
Published functional studies demonstrate showed that p.(P11R) reduced the enzymatic activity to about 31% of the wild-type (PMID: 22821680); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32102150, 19479957, 31589614, 28904440, 33691640, 22821680, 32556641, 33721035, 35149915, 31328266, 32508047, Saha[article]2021, 37464296, 37306718, 38977330, 30341509, 32792227, 37874369) (less)
|
|
|
Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050615.5
First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024 |
Comment:
AGXT: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
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: SCV000239600.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Result:
In vitro activity: <2% on major and minor allele.
|
|
|
Pathogenic
(Nov 12, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469157.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
|
Likely pathogenic
(Apr 04, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002076450.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Aug 26, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
paternal,
biparental
|
Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University
Accession: SCV005368637.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Variant_type:missense/MutationTaster:Disease_causing/CADD:Damaging/phyloP:Conserved/phastCons:Nonconserved/gnomAD_exome_EastAsian:0.0014/ExAC_EastAsian:-/dbSNP:rs34116584
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Asian
Geographic origin: China
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Asian
Geographic origin: China
|
|
|
Uncertain significance
(Mar 25, 2024)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805405.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the AGXT protein (p.Pro11Arg). This variant is present in population databases (rs34116584, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 22821680, 32556641). 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: 204069). 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 95%. Experimental studies have shown that this missense change affects AGXT function (PMID: 22821680). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate showed that p.(P11R) reduced the enzymatic activity to about 31% of the wild-type (PMID: 22821680); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32102150, 19479957, 31589614, 28904440, 33691640, 22821680, 32556641, 33721035, 35149915, 31328266, 32508047, Saha[article]2021, 37464296, 37306718, 38977330, 30341509, 32792227, 37874369)
Comment:
AGXT: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Comment:
Variant_type:missense/MutationTaster:Disease_causing/CADD:Damaging/phyloP:Conserved/phastCons:Nonconserved/gnomAD_exome_EastAsian:0.0014/ExAC_EastAsian:-/dbSNP:rs34116584
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:
Variant summary: AGXT c.32C>G (p.Pro11Arg) results in a non-conservative amino acid change in 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 0.00016 in 246986 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00016 vs 0.0024), allowing no conclusion about variant significance. c.32C>G has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009, Tammachote_2012, Krishnamurthy_2017, Zhao_2020, Lin_2021, Saha_2023). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact on protein function and results in reduced the enzymatic activity (Williams_2009, Tammachote_2012). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the AGXT protein (p.Pro11Arg). This variant is present in population databases (rs34116584, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 22821680, 32556641). 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: 204069). 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 95%. Experimental studies have shown that this missense change affects AGXT function (PMID: 22821680). For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate showed that p.(P11R) reduced the enzymatic activity to about 31% of the wild-type (PMID: 22821680); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32102150, 19479957, 31589614, 28904440, 33691640, 22821680, 32556641, 33721035, 35149915, 31328266, 32508047, Saha[article]2021, 37464296, 37306718, 38977330, 30341509, 32792227, 37874369)
Comment:
AGXT: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting
Comment:
Variant_type:missense/MutationTaster:Disease_causing/CADD:Damaging/phyloP:Conserved/phastCons:Nonconserved/gnomAD_exome_EastAsian:0.0014/ExAC_EastAsian:-/dbSNP:rs34116584
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical utility of genetic testing in Indian children with kidney diseases. | Saha A | BMC nephrology | 2023 | PMID: 37464296 |
| Use of whole-exome sequencing to identify novel monogenic gene mutations and genotype-phenotype correlations in Chinese Han children with urolithiasis. | Wang Z | Frontiers in genetics | 2023 | PMID: 37144129 |
| Clinical analysis of 13 children with primary hyperoxaluria type 1. | Lin JA | Urolithiasis | 2021 | PMID: 33721035 |
| A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome. | Xu CB | BMC nephrology | 2021 | PMID: 33691640 |
| Characteristics of the genotype and phenotype in Chinese primary hyperoxaluria type 1 populations. | Zhao F | Urolithiasis | 2021 | PMID: 32556641 |
| The ILE56 mutation on different genetic backgrounds of alanine:glyoxylate aminotransferase: Clinical features and biochemical characterization. | Dindo M | Molecular genetics and metabolism | 2020 | PMID: 32792227 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Updated Genetic Testing of Primary Hyperoxaluria Type 1 in a Chinese Population: Results from a Single Center Study and a Systematic Review. | Du DF | Current medical science | 2018 | PMID: 30341509 |
| Primary Hyperoxaluria Type 1 with Homozygosity for a Double-mutated AGXT Allele in a 2-year-old Child. | Krishnamurthy S | Indian journal of nephrology | 2017 | PMID: 28904440 |
| Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2. | Tammachote R | American journal of medical genetics. Part A | 2012 | PMID: 22821680 |
| 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 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs34116584 ...
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 10, 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.