2-240875964-T-C

Position:

• chr2-240875964-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000030.3(AGXT):​c.806T>C​(p.Leu269Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.06

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-240875964-T-C is Pathogenic according to our data. Variant chr2-240875964-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204128.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.806T>C	p.Leu269Pro	missense_variant	8/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.806T>C	p.Leu269Pro	missense_variant	8/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000476698.1	n.458T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects AGXT function (PMID: 24718375). 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. ClinVar contains an entry for this variant (Variation ID: 204128). This missense change has been observed in individual(s) with clinical features of primary hyperoxaluria (PMID: 19479957; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 269 of the AGXT protein (p.Leu269Pro). -

Primary hyperoxaluria, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Biochemistry Laboratory, Health Services Laboratory

Oct 27, 2023

Reduced AGT activity in vitro (PMID:24718375). ACMG: PS3 PM2 PM3 PP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 11, 2022

Variant summary: AGXT c.806T>C (p.Leu269Pro) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes (gnomAD). c.806T>C has been reported in the literature in at least one individual presumably affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009). This report does not provide unequivocal conclusions about association of the variant with Primary Hyperoxaluria Type 1. One publication reports experimental evidence evaluating an impact on protein function. The variant protein was found to have <5% of normal activity and stability with both the minor and major alleles of AGXT in a yeast cell-based assay system (e.g. Lage_2014). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, until additional evidence of clinical and/or functional importance becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.67
Sift	Benign	0.082	T
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.95		Loss of stability (P = 0.0492);
MVP		0.96
MPC		0.29
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177271; hg19: chr2-241815381;