VCV000005648.13 - ClinVar

NM_000030.3(AGXT):c.698G>A (p.Arg233His)

Germline

Classification

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.

(6)

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

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.698G>A (p.Arg233His)

Variation ID: 5648 Accession: VCV000005648.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240875126 (GRCh38) [ NCBI UCSC ] 2: 241814543 (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	Jun 17, 2024	Feb 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000030.3:c.698G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000021.1:p.Arg233His	missense
NC_000002.12:g.240875126G>A
NC_000002.11:g.241814543G>A
NG_008005.1:g.11382G>A
	P21549:p.Arg233His

... more HGVS ... less HGVS

Protein change

R233H

Other names

Canonical SPDI

NC_000002.12:240875125:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00005

The Genome Aggregation Database (gnomAD) 0.00006

Links

ClinGen: CA253545 UniProtKB: P21549#VAR_008880 OMIM: 604285.0009 dbSNP: rs121908527 VarSome

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
Gene	OMIM	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.
Primary hyperoxaluria, type I	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 26, 2024	RCV000006002.19
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2023	RCV001385647.15

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 (May 24, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486360.2 First in ClinVar: Nov 10, 2016 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 25629080‚ 17495019‚ 18448374‚ 24988064‚ 9192270
Pathogenic (Mar 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810968.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001585584.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 9192270‚ 17495019‚ 25629080‚ 18448374‚ 18282470 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the AGXT protein (p.Arg233His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the AGXT protein (p.Arg233His). This variant is present in population databases (rs121908527, gnomAD 0.008%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 9192270, 17495019, 25629080). ClinVar contains an entry for this variant (Variation ID: 5648). 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: 17495019, 18448374). This variant disrupts the p.Arg233 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9192270, 17495019, 18282470, 18448374, 25629080). 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)
Pathogenic (Feb 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary hyperoxaluria, type I Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004192275.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
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: SCV000239671.1 First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015	Publications: PubMed (2) PubMed: 9192270‚ 17495019 Other databases http://www.uclh.nhs.uk/OurServic… http://www.uclh.nhs.uk/OurServices/ServiceA-Z/PATH/PATHBIOMED/CBIO/Documents/AGXT%20mutation%20database.pdf Result: In vitro activity: <1% on minor allele; 14% on major.
Pathogenic (Jun 01, 1997)	no assertion criteria provided Method: literature only	HYPEROXALURIA, PRIMARY, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026184.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 04, 2016	Publications: PubMed (1) PubMed: 9192270 Comment on evidence: See 604285.0008 and von Schnakenburg and Rumsby (1997).

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the AGXT protein (p.Arg233His). This variant is present in population databases (rs121908527, gnomAD 0.008%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 9192270, 17495019, 25629080). ClinVar contains an entry for this variant (Variation ID: 5648). 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: 17495019, 18448374). This variant disrupts the p.Arg233 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9192270, 17495019, 18282470, 18448374, 25629080). 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Partial trypsin digestion as an indicator of mis-folding of mutant alanine:glyoxylate aminotransferase and chaperone effects of specific ligands. Study of a spectrum of missense mutants.	Coulter-Mackie MB	Molecular genetics and metabolism	2008	PMID: 18448374
Mutation-based diagnostic testing for primary hyperoxaluria type 1: survey of results.	Coulter-Mackie MB	Clinical biochemistry	2008	PMID: 18282470
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
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	-	-	-	-

Text-mined citations for rs121908527 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000030.3(AGXT):c.698G>A (p.Arg233His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908527 ...