NM_000030.3:c.508G>C

Variant names:

• chr2-240871433-G-C
• rs121908529
• NM_000030.3:c.508G>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000030.3(AGXT):​c.508G>C​(p.Gly170Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.49

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.

• PS1: Transcript NM_000030.3 (AGXT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-240871433-G-C is Pathogenic according to our data. Variant chr2-240871433-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2710435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.508G>C	p.Gly170Arg	missense_variant	Exon 4 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.508G>C	p.Gly170Arg	missense_variant	Exon 4 of 11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000472436.1	n.528G>C		non_coding_transcript_exon_variant	Exon 4 of 5	2
AGXT	ENST00000476698.1	n.245G>C		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria Pathogenic:1

Jun 20, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGXT c.508G>C (p.Gly170Arg) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210718 control chromosomes. To our knowledge, no occurrence of c.508G>C in individuals affected with Primary Hyperoxaluria Type 1 have been reported. A different variant resulting in the same amino acid consequence has been classified as pathogenic by our lab (c.508G>A), supporting the pathogenicity of this variant. ClinVar contains an entry for this variant (Variation ID: 2710435). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Jan 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 170 of the AGXT protein (p.Gly170Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 11708860, 15356974, 15840016, 20016466, 24988064). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 10960483, 17110443, 23229545). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at G170 (P = 0.1531);
MVP		0.95
MPC		0.26
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908529; hg19: chr2-241810850;