rs180177221

chr2-240871369-AGTGCTGCT-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000030.3(AGXT):c.447_454del(p.Leu151AsnfsTer14) variant causes a frameshift change. 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:7
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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	UniProt
AGXT	NM_000030.3	c.447_454del	p.Leu151AsnfsTer14	frameshift_variant	4/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.447_454del	p.Leu151AsnfsTer14	frameshift_variant	4/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.467_474del		non_coding_transcript_exon_variant	4/5	2
AGXT	ENST00000476698.1	n.184_191del		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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:5

Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 18, 2016	- -

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

Invitae

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;