2-240875159-T-C

Variant names:

Variant summary

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

The NM_000030.3(AGXT):c.731T>C(p.Ile244Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,868 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: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.29

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:

Genome browser will be placed here

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, 0.992

PP5

Variant 2-240875159-T-C is Pathogenic according to our data. Variant chr2-240875159-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5646.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.731T>C	p.Ile244Thr	missense_variant	Exon 7 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.731T>C	p.Ile244Thr	missense_variant	Exon 7 of 11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000476698.1 link	n.383T>C		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251428

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

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:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

0.0000180

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00143

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:9Other:1

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 14, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000030.2(AGXT):c.731T>C(I244T) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 23229545, 10960483, 9192270, 10541294, 24988064, 24012869, 16912707 and 12777626. Classification of NM_000030.2(AGXT):c.731T>C(I244T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jun 03, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005646, PMID:9192270). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9192270). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 23229545). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.733>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the AGXT protein (p.Ile244Thr). This variant is present in population databases (rs121908525, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperoxaluria (PMID: 9192270). ClinVar contains an entry for this variant (Variation ID: 5646). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AGXT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 23229545). For these reasons, this variant has been classified as Pathogenic. -

Apr 30, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate that in the absence of the P11L risk allele, I244T mutant AGT protein is soluble and catalytically active; however, in the presence of the P11L risk allele in cis with the I244T variant, the AGT protein is misrouted to the mitochondria, resulting in protein aggregation into inclusion bodies (Lumb et al., 2000; Fargue et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31905342, 29456205, 24012869, 28906061, 28893421, 26161999, 27135212, 24988064, 22844106, 12777626, 9192270, 24205397, 23229545, 10960483, 18782763, 23597595) -

AGXT-related disorder

Pathogenic:1

Dec 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AGXT c.731T>C variant is predicted to result in the amino acid substitution p.Ile244Thr. This variant has been reported in the homozygous or compound heterozygous state in many individuals with primary hyperoxaluria type 1 and is one of the most frequent causative variants (Mandrile et al. 2014. PubMed ID: 24988064; Ahmed et al. 2022. PubMed ID: 35661454; Monico et al. 2007. PubMed ID: 17460142; Rhuma et al. 2018. PubMed ID: 29456205). A large Libyan cohort study of individuals with primary hyperoxaluria type 1 indicated this was a founder variant in this population (Rhuma et al. 2018. PubMed ID: 29456205). Of note, the p.Ile244Thr variant is many times observed with a common variant, c.32C>T p.Pro11Leu. Functional studies indicate that the Pro11Leu variant modifies the effect of the p.Ile244Thr and reduces protein activity and localization (Santana et al. 2003. PubMed ID: 12777626 ; Fargue et al. 2013. PubMed ID: 23229545; Dindo et al. 2017. PubMed ID: 28906061). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241814576-T-C). This variant is interpreted as pathogenic for autosomal recessive AGXT-related disorders. -

Nephrocalcinosis;C0392525:Nephrolithiasis

Pathogenic:1

Sep 08, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary hyperoxaluria

Pathogenic:1

May 07, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The AGXT c.731T>C (p.Ile244Thr) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121328 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717). Multiple publications have cited the variant in affected indiviudals and has been implicated to be a Spain founder mutation. As would be expected of a founder effect, other polymorphisms and regional microsatellites within the AGXT gene are shared in this founder haplotype and have been reported to further modify the effect of this variant. Functional studies have shown that the variant alone acts comparable to wild type enzymatic activity (Santana_2003 and Lumb_2000), however, in cis with another variant, in particular, P11L, the enzymatic activity is loss. Rumsby_2004 found that homozygous individuals had limited enzymatic activity, although it is unclear whether the commonly found P11L was found in cis with these individuals. Furthermore, Rumsby_2004, citing the study by Santana_2003, states that c.731T>C mutation has approximately 50% of normal activity when expressed with Pro11 but less than 5% of activity when expressed with Leu11. At-least one additional report by Monico_2007 cites a patient diagnosed at age 1 to be compound heterozygous for this variant and another pathogenic variant described as IVS8-3C>G (c.847-3C>G in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic, but should be noted that the variant of interest seems to be influenced by particular variants observed in cis. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Benign

0.15

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0060

Sift4G

Benign

0.099

Polyphen

0.45

Vest4

0.77

MutPred

0.87

Loss of stability (P = 0.0095);

MVP

0.89

MPC

0.24

ClinPred

0.50

GERP RS

3.8

Varity_R

0.48

gMVP

0.84

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

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