Genetic Variant AGXT:p.Ser205Leu (chr2-240873996-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000030.3(AGXT):c.614C>T(p.Ser205Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.33

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 2-240873996-C-T is Pathogenic according to our data. Variant chr2-240873996-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 204118.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 link	c.614C>T	p.Ser205Leu	missense_variant	Exon 6 of 11	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 link	c.614C>T	p.Ser205Leu	missense_variant	Exon 6 of 11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000476698.1 link	n.332+947C>T		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251126

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461356

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000648

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:4

Feb 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

Aug 26, 2024

Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant_type:missense/MutationTaster:Disease_causing/CADD:Damaging/phyloP:Conserved/phastCons:Nonconserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs180177248 -

Primary hyperoxaluria

Pathogenic:1

Oct 11, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGXT c.614C>T (p.Ser205Leu) 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 allele was found at a frequency of 4e-06 in 251126 control chromosomes. c.614C>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Primary Hyperoxaluria Type 1 (example, Li_2018, Birtel_2019, Chen_2021, Zhao_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Williams_2009). The most pronounced variant effect results in <3% of normal alanine:glyoxylate aminotransferase (AGT) activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Apr 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 205 of the AGXT protein (p.Ser205Leu). This variant is present in population databases (rs180177248, gnomAD 0.0009%). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 27935012, 30541997, 32556641). ClinVar contains an entry for this variant (Variation ID: 204118). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser205 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2039493; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects AGXT function (PMID: 19479957). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.89

MVP

0.95

MPC

0.24

ClinPred

0.98

GERP RS

4.1

Varity_R

0.87

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over