rs180177221

Positions:

• chr2-240871369-AGTGCTGCT-A

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.447_454delGCTGCTGT​(p.Leu151fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGXT NM_000030.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.82

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]

AGXT (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-240871369-AGTGCTGCT-A is Pathogenic according to our data. Variant chr2-240871369-AGTGCTGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 204185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.447_454delGCTGCTGT	p.Leu151fs	frameshift_variant	4/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.447_454delGCTGCTGT	p.Leu151fs	frameshift_variant	4/11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000472436.1	n.467_474delGCTGCTGT		non_coding_transcript_exon_variant	4/5	2
AGXT	ENST00000476698.1	n.184_191delGCTGCTGT		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 23, 2024	- -
Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed frameshift c.447_454delp.Leu151AsnfsTer14 variant in AGXT gene has been reported previously in individuals affected with Primary Hyperoxaluria Type 1 Dutta AK, et al., 2016; Williams E, Rumsby G., 2007. The p.Leu151AsnfsTer14 variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Leucine 151, changes this amino acid to Asparagine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Leu151AsnfsTer14. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Primary hyperoxaluria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 30, 2019

Variant summary: AGXT c.447_454delGCTGCTGT (p.Leu151AsnfsX14) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 213810 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals (primarily of Asian origin) affected with Primary Hyperoxaluria Type 1 (Williams_2007, Dutta_2016). These data indicate that the variant is very likely to be associated with disease. Enzymatic activity measured from a homozygous individual harboring this variant show 6% of mean control activity (Williams_2007). A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2023

This sequence change creates a premature translational stop signal (p.Leu151Asnfs*14) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary hyperoxaluria (PMID: 17495019, 27512303). This variant is also known as c.445_452delGTGCTGCT. ClinVar contains an entry for this variant (Variation ID: 204185). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177221; hg19: chr2-241810786;