Variant summary: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121328 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). Multiple publications have cited the variant in affected indiviudals and has been implicated to be a Spain founder mutation. As would be expected of a founder effect, other polymorphisms and regional microsatellites within the AGXT gene are shared in this founder haplotype and have been reported to further modify the effect of this variant. Functional studies have shown that the variant alone acts comparable to wild type enzymatic activity (Santana_2003 and Lumb_2000), however, in cis with another variant, in particular, P11L, the enzymatic activity is loss. Rumsby_2004 found that homozygous individuals had limited enzymatic activity, although it is unclear whether the commonly found P11L was found in cis with these individuals. Furthermore, Rumsby_2004, citing the study by Santana_2003, states that c.731T>C mutation has approximately 50% of normal activity when expressed with Pro11 but less than 5% of activity when expressed with Leu11. At-least one additional report by Monico_2007 cites a patient diagnosed at age 1 to be compound heterozygous for this variant and another pathogenic variant described as IVS8-3C>G (c.847-3C>G in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic, but should be noted that the variant of interest seems to be influenced by particular variants observed in cis.
ClinVar Genomic variation as it relates to human health
NM_000030.3(AGXT):c.731T>C (p.Ile244Thr)
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.
(15)
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
15
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.731T>C (p.Ile244Thr)
Variation ID: 5646 Accession: VCV000005646.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240875159 (GRCh38) [ NCBI UCSC ] 2: 241814576 (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 Mar 24, 2015 Oct 8, 2024 Mar 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000030.3:c.731T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000021.1:p.Ile244Thr missense NC_000002.12:g.240875159T>C NC_000002.11:g.241814576T>C NG_008005.1:g.11415T>C P21549:p.Ile244Thr - Protein change
- I244T
- Other names
- -
- Canonical SPDI
- NC_000002.12:240875158:T: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) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
- 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 (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2024 | RCV000006000.28 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 7, 2017 | RCV000586265.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Sep 8, 2017 | RCV000662316.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV001042614.16 | |
|
AGXT-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 5, 2023 | RCV003407286.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 07, 2017)
|
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: SCV000693980.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this … (more)
Variant summary: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121328 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). Multiple publications have cited the variant in affected indiviudals and has been implicated to be a Spain founder mutation. As would be expected of a founder effect, other polymorphisms and regional microsatellites within the AGXT gene are shared in this founder haplotype and have been reported to further modify the effect of this variant. Functional studies have shown that the variant alone acts comparable to wild type enzymatic activity (Santana_2003 and Lumb_2000), however, in cis with another variant, in particular, P11L, the enzymatic activity is loss. Rumsby_2004 found that homozygous individuals had limited enzymatic activity, although it is unclear whether the commonly found P11L was found in cis with these individuals. Furthermore, Rumsby_2004, citing the study by Santana_2003, states that c.731T>C mutation has approximately 50% of normal activity when expressed with Pro11 but less than 5% of activity when expressed with Leu11. At-least one additional report by Monico_2007 cites a patient diagnosed at age 1 to be compound heterozygous for this variant and another pathogenic variant described as IVS8-3C>G (c.847-3C>G in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic, but should be noted that the variant of interest seems to be influenced by particular variants observed in cis. (less)
|
|
|
Pathogenic
(Apr 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001766228.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Functional studies demonstrate that in the absence of the P11L risk allele, I244T mutant AGT protein is soluble and catalytically active; however, in the presence … (more)
Functional studies demonstrate that in the absence of the P11L risk allele, I244T mutant AGT protein is soluble and catalytically active; however, in the presence of the P11L risk allele in cis with the I244T variant, the AGT protein is misrouted to the mitochondria, resulting in protein aggregation into inclusion bodies (Lumb et al., 2000; Fargue et al., 2013); 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: 31905342, 29456205, 24012869, 28906061, 28893421, 26161999, 27135212, 24988064, 22844106, 12777626, 9192270, 24205397, 23229545, 10960483, 18782763, 23597595) (less)
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318496.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005646, PMID:9192270). … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005646, PMID:9192270). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9192270). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 23229545). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.733>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hyperoxaluria (present) , Nephrolithiasis (present)
|
|
|
Pathogenic
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003809015.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194561.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194209.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000030.2(AGXT):c.731T>C(I244T) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 23229545, 10960483, 9192270, 10541294, … (more)
NM_000030.2(AGXT):c.731T>C(I244T) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 23229545, 10960483, 9192270, 10541294, 24988064, 24012869, 16912707 and 12777626. Classification of NM_000030.2(AGXT):c.731T>C(I244T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002792762.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
Eurofins-Biomnis
Accession: SCV003935043.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
|
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206309.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the AGXT protein (p.Ile244Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the AGXT protein (p.Ile244Thr). This variant is present in population databases (rs121908525, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 9192270). ClinVar contains an entry for this variant (Variation ID: 5646). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 23229545). For these reasons, this variant has been classified as Pathogenic. (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: SCV000239674.1
First in ClinVar: Jul 23, 2015 Last updated: Jul 23, 2015 |
Result:
In vitro activity: <1% on minor allele; 50% on major.
|
|
|
Pathogenic
(Jan 25, 2013)
|
no assertion criteria provided
Method: literature only
|
HYPEROXALURIA, PRIMARY, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026182.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2015 |
Comment on evidence:
One of the mutations clustered in exon 7 of the AGXT gene identified by von Schnakenburg and Rumsby (1997) in studies of 79 patients with … (more)
One of the mutations clustered in exon 7 of the AGXT gene identified by von Schnakenburg and Rumsby (1997) in studies of 79 patients with type I primary hyperoxaluria (PH1; 259900) was an 853T-C transition that led to a predicted ile244-to-thr (I244T) substitution. This was found in homozygous or heterozygous state in 9% of patients, making it the second most common mutation found up to that time. Santana et al. (2003) reported that most of the AGXT alleles detected in patients from the Canary Islands with PH1 carry the I244T mutation; 14 of 16 patients they studied were homozygous for this mutation and shared in their haplotypes 4 polymorphisms within AGXT and regional microsatellites (AGXT*LTM), consistent with a founder effect. Santana et al. (2003) investigated the consequence of these amino acid changes and found that although I244T alone did not affect AGXT activity or subcellular localization (i.e., mitochondria vs peroxisomes), when present in the same protein molecule as L11P (see 604285.0002), it resulted in loss of enzymatic activity in soluble cell extracts. Like its normal counterpart, the AGXT*LTM protein was present in the peroxisomes but was insoluble in detergent-free buffers. The L11P polymorphism behaved as an intragenic modifier of the I244T mutation, with the resulting protein undergoing stable interaction with molecular chaperones and temperature-sensitive aggregation. Among various chemical chaperones tested in cell culture, betaine substantially improved the solubility of the mutant protein and the enzymatic activity in cell lysates. Santana et al. (2003) concluded that the synergistic effect of P11L with I244T causes PH1, a protein conformational disease. Fargue et al. (2013) found that the I244T mutation, on the background of the minor allele, can unmask the cryptic P11L-generated mitochondrial targeting sequence and results in AGT protein being mistargeted to mitochondria. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001460162.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Dec 05, 2023)
|
no assertion criteria provided
Method: clinical testing
|
AGXT-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004110893.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The AGXT c.731T>C variant is predicted to result in the amino acid substitution p.Ile244Thr. This variant has been reported in the homozygous or compound heterozygous … (more)
The AGXT c.731T>C variant is predicted to result in the amino acid substitution p.Ile244Thr. This variant has been reported in the homozygous or compound heterozygous state in many individuals with primary hyperoxaluria type 1 and is one of the most frequent causative variants (Mandrile et al. 2014. PubMed ID: 24988064; Ahmed et al. 2022. PubMed ID: 35661454; Monico et al. 2007. PubMed ID: 17460142; Rhuma et al. 2018. PubMed ID: 29456205). A large Libyan cohort study of individuals with primary hyperoxaluria type 1 indicated this was a founder variant in this population (Rhuma et al. 2018. PubMed ID: 29456205). Of note, the p.Ile244Thr variant is many times observed with a common variant, c.32C>T p.Pro11Leu. Functional studies indicate that the Pro11Leu variant modifies the effect of the p.Ile244Thr and reduces protein activity and localization (Santana et al. 2003. PubMed ID: 12777626 ; Fargue et al. 2013. PubMed ID: 23229545; Dindo et al. 2017. PubMed ID: 28906061). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241814576-T-C). This variant is interpreted as pathogenic for autosomal recessive AGXT-related disorders. (less)
|
|
|
Likely pathogenic
(Sep 08, 2017)
|
no assertion criteria provided
Method: literature only
|
Nephrolithiasis
Nephrocalcinosis
Affected status: yes
Allele origin:
germline
|
Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784648.1
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Primary hyperoxaluria, type I
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000172457.3
First in ClinVar: Jul 24, 2014 Last updated: Oct 01, 2022 |
|
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Comment:
Comment:
Functional studies demonstrate that in the absence of the P11L risk allele, I244T mutant AGT protein is soluble and catalytically active; however, in the presence of the P11L risk allele in cis with the I244T variant, the AGT protein is misrouted to the mitochondria, resulting in protein aggregation into inclusion bodies (Lumb et al., 2000; Fargue et al., 2013); 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: 31905342, 29456205, 24012869, 28906061, 28893421, 26161999, 27135212, 24988064, 22844106, 12777626, 9192270, 24205397, 23229545, 10960483, 18782763, 23597595)
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005646, PMID:9192270). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9192270). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 23229545). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.733>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
NM_000030.2(AGXT):c.731T>C(I244T) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 23229545, 10960483, 9192270, 10541294, 24988064, 24012869, 16912707 and 12777626. Classification of NM_000030.2(AGXT):c.731T>C(I244T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the AGXT protein (p.Ile244Thr). This variant is present in population databases (rs121908525, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 9192270). ClinVar contains an entry for this variant (Variation ID: 5646). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 23229545). For these reasons, this variant has been classified as Pathogenic.
Comment:
The AGXT c.731T>C variant is predicted to result in the amino acid substitution p.Ile244Thr. This variant has been reported in the homozygous or compound heterozygous state in many individuals with primary hyperoxaluria type 1 and is one of the most frequent causative variants (Mandrile et al. 2014. PubMed ID: 24988064; Ahmed et al. 2022. PubMed ID: 35661454; Monico et al. 2007. PubMed ID: 17460142; Rhuma et al. 2018. PubMed ID: 29456205). A large Libyan cohort study of individuals with primary hyperoxaluria type 1 indicated this was a founder variant in this population (Rhuma et al. 2018. PubMed ID: 29456205). Of note, the p.Ile244Thr variant is many times observed with a common variant, c.32C>T p.Pro11Leu. Functional studies indicate that the Pro11Leu variant modifies the effect of the p.Ile244Thr and reduces protein activity and localization (Santana et al. 2003. PubMed ID: 12777626 ; Fargue et al. 2013. PubMed ID: 23229545; Dindo et al. 2017. PubMed ID: 28906061). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241814576-T-C). This variant is interpreted as pathogenic for autosomal recessive AGXT-related disorders.
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: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121328 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). Multiple publications have cited the variant in affected indiviudals and has been implicated to be a Spain founder mutation. As would be expected of a founder effect, other polymorphisms and regional microsatellites within the AGXT gene are shared in this founder haplotype and have been reported to further modify the effect of this variant. Functional studies have shown that the variant alone acts comparable to wild type enzymatic activity (Santana_2003 and Lumb_2000), however, in cis with another variant, in particular, P11L, the enzymatic activity is loss. Rumsby_2004 found that homozygous individuals had limited enzymatic activity, although it is unclear whether the commonly found P11L was found in cis with these individuals. Furthermore, Rumsby_2004, citing the study by Santana_2003, states that c.731T>C mutation has approximately 50% of normal activity when expressed with Pro11 but less than 5% of activity when expressed with Leu11. At-least one additional report by Monico_2007 cites a patient diagnosed at age 1 to be compound heterozygous for this variant and another pathogenic variant described as IVS8-3C>G (c.847-3C>G in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic, but should be noted that the variant of interest seems to be influenced by particular variants observed in cis.
Comment:
Functional studies demonstrate that in the absence of the P11L risk allele, I244T mutant AGT protein is soluble and catalytically active; however, in the presence of the P11L risk allele in cis with the I244T variant, the AGT protein is misrouted to the mitochondria, resulting in protein aggregation into inclusion bodies (Lumb et al., 2000; Fargue et al., 2013); 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: 31905342, 29456205, 24012869, 28906061, 28893421, 26161999, 27135212, 24988064, 22844106, 12777626, 9192270, 24205397, 23229545, 10960483, 18782763, 23597595)
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005646, PMID:9192270). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9192270). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 23229545). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.733>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
NM_000030.2(AGXT):c.731T>C(I244T) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 23229545, 10960483, 9192270, 10541294, 24988064, 24012869, 16912707 and 12777626. Classification of NM_000030.2(AGXT):c.731T>C(I244T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the AGXT protein (p.Ile244Thr). This variant is present in population databases (rs121908525, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 9192270). ClinVar contains an entry for this variant (Variation ID: 5646). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 23229545). For these reasons, this variant has been classified as Pathogenic.
Comment:
The AGXT c.731T>C variant is predicted to result in the amino acid substitution p.Ile244Thr. This variant has been reported in the homozygous or compound heterozygous state in many individuals with primary hyperoxaluria type 1 and is one of the most frequent causative variants (Mandrile et al. 2014. PubMed ID: 24988064; Ahmed et al. 2022. PubMed ID: 35661454; Monico et al. 2007. PubMed ID: 17460142; Rhuma et al. 2018. PubMed ID: 29456205). A large Libyan cohort study of individuals with primary hyperoxaluria type 1 indicated this was a founder variant in this population (Rhuma et al. 2018. PubMed ID: 29456205). Of note, the p.Ile244Thr variant is many times observed with a common variant, c.32C>T p.Pro11Leu. Functional studies indicate that the Pro11Leu variant modifies the effect of the p.Ile244Thr and reduces protein activity and localization (Santana et al. 2003. PubMed ID: 12777626 ; Fargue et al. 2013. PubMed ID: 23229545; Dindo et al. 2017. PubMed ID: 28906061). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241814576-T-C). This variant is interpreted as pathogenic for autosomal recessive AGXT-related disorders.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary Hyperoxaluria Type 1. | Adam MP | - | 2024 | PMID: 20301460 |
| Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. | Daga A | Kidney international | 2018 | PMID: 28893421 |
| 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 |
| A double mutation in AGXT gene in families with primary hyperoxaluria type 1. | Kanoun H | Gene | 2013 | PMID: 24012869 |
| 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 |
| 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 |
| Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: Single-center experience. | Lorenzo V | Kidney international | 2006 | PMID: 16912707 |
| Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. | Rumsby G | Kidney international | 2004 | PMID: 15327387 |
| 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 |
| Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. | Rinat C | Journal of the American Society of Nephrology : JASN | 1999 | PMID: 10541294 |
| Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene. | von Schnakenburg C | Journal of medical genetics | 1997 | PMID: 9192270 |
| http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf | - | - | - | - |
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Text-mined citations for rs121908525 ...
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Record last updated Nov 19, 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.