2-240868890-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000030.3(AGXT):c.33dup(p.Lys12GlnfsTer156) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,610,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: AGXT NM_000030.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 0.775

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 247 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-240868890-A-AC is Pathogenic according to our data. Variant chr2-240868890-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 140583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.33dup	p.Lys12GlnfsTer156	frameshift_variant	1/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.33dup	p.Lys12GlnfsTer156	frameshift_variant	1/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.53dup		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 19 AN: 151008 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1459284 Hom.: 0 Cov.: 31 AF XY: 0.000167 AC XY: 121 AN XY: 725858

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.000249

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151122 Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 9 AN XY: 73852

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:17 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000140583). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jan 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Nov 11, 2021	PVS1, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 17495019. Classification of NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2022	- -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozgous c.33dupC variant was identified by our study in one individual with Hyperoxaluria. The c.33dupC is a well-established known pathogenic variant (https://www.ncbi.nlm.nih.gov/books/NBK1283/) and loss of function is a known mechanism of disease in the AGXT gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	Mar 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift AGXT (p.Lys12GlnfsTer156) is one of the most common variant reported in individuals affected with primary hyperoxaluria (Rumsby G. et. al., 2004; Williams EL et. al., 2009). This variant has been reported previously in homozygous state in patients affected with Hyperoxaluria, primary, type 1 (Theodossiadis, P. G. et. al., 2002). The p.Lys12GlnfsTer156 variant is novel (not in any individuals) in 1000 Genomes. This variant causes a frameshift starting with codon Lysine 12, changes this amino acid to Glutamine residue, and creates a premature stop codon at position 156 of the new reading frame, denoted p.Lys12GlnfsTer156. This variant has been reported to the ClinVar database as Pathogenic. Loss-of-function variant in AGXT are known to be Pathogenic (Williams EL et. al., 2009). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type 1 (MIM#259900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 19 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It accounts for approximately 30% of disease-causing alleles and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Lys12Glnfs*156) in the AGXT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). 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 premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 15327387, 19479957, 25629080, 27135212). This variant is also known as 33_34insC. ClinVar contains an entry for this variant (Variation ID: 140583). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32556641, 31980526, 15110324, 31102713, 29127259, 29456205, 30655312, 30341509, 28619084, 10453743, 20549407, 16931222, 27135212, 28969594) -

AGXT-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2023

The AGXT c.33dupC variant is predicted to result in a frameshift and premature protein termination (p.Lys12Glnfs*156). This variant has been reported to be pathogenic for primary hyperoxaluria (Mayordomo-Colunga et al. 2011. PubMed ID: 20549407). This variant is reported in 0.026% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241808307-A-AC). Frameshift variants in AGXT are expected to be pathogenic. This variant is interpreted as pathogenic. -

Primary hyperoxaluria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 24, 2018

Variant summary: AGXT c.33dupC (p.Lys12GlnfsX156) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 30572 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00047 vs 0.0024), allowing no conclusion about variant significance. c.33dupC has been reported in the literature in a multiple affected individuals with Primary Hyperoxaluria Type 1 (Rumsby_2004, Mbarek_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Rumsby 2004). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 10, 2017

- -

Alanine glyoxylate aminotransferase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

This sequence change in AGXT is a frameshift variant predicted to cause a premature stop codon, p.(Lys12Glnfs*156), in biologically relevant exon 4/11 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.02% (1/4,750 alleles) in the South Asian population, which is consistent with recessive disease. The variant is one of the most commonly reported pathogenic variants in AGXT. It has been identified in the homozygous state and compound heterozygous with a second pathogenic variant in multiple individuals with clinical/biochemical diagnosis of primary hyperoxaluria (PMID: 15110324, 20301460). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs180177201; hg19: chr2-241808307;