chr2-240869246-C-T
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.242C>T(p.Ser81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,580 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
AGXT
NM_000030.3 missense
NM_000030.3 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 5.54
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]
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, 0.995
PP5
Variant 2-240869246-C-T is Pathogenic according to our data. Variant chr2-240869246-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251240Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135838
GnomAD3 exomes
AF:
AC:
3
AN:
251240
Hom.:
AF XY:
AC XY:
3
AN XY:
135838
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461580Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727098
GnomAD4 exome
AF:
AC:
2
AN:
1461580
Hom.:
Cov.:
34
AF XY:
AC XY:
2
AN XY:
727098
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2024 | - - |
| Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | AGXT: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 26, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 81 of the AGXT protein (p.Ser81Leu). This variant is present in population databases (rs180177184, gnomAD 0.007%). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 20564000, 24988064). ClinVar contains an entry for this variant (Variation ID: 204083). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 24990153). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2024 | The c.242C>T (p.S81L) alteration is located in exon 2 (coding exon 2) of the AGXT gene. This alteration results from a C to T substitution at nucleotide position 242, causing the serine (S) at amino acid position 81 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251240) total alleles studied. The highest observed frequency was 0.006% (1/16242) of African alleles. This alteration was detected in conjunction with another alteration in AGXT, in multiple individuals with AGXT-related primary hyperoxaluria (Montioli, 2014; Mandrile, 2014). This amino acid position is not well conserved in available vertebrate species. In an assay testing AGXT function, this variant showed a functionally abnormal result (Montioli, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Primary hyperoxaluria Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2022 | Variant summary: AGXT c.242C>T (p.Ser81Leu) results in a non-conservative amino acid change in 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 1.2e-05 in 251240 control chromosomes (gnomAD). The variant, c.242C>T, has been reported in the literature in compound heterozygous individuals affected with Primary Hyperoxaluria Type 1(Montioli_2014, Williams_2009, Mandrile_2014); the variant was noted to be found on the major allele, and was described to be associated with an earlier onset of end-stage renal disease (ESRD) when it occurred in trans with a null mutation, compared to when occurring in trans with the p.G170R mutation (Montioli_2014, Mandrile_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't affect the expression level of the protein, however, it resulted in a severely decreased pyridoxal phosphate binding, with less than ~5% residual activity in the absence of PLP, while in the presence of PLP the specific activity was ~20% of the WT (Montioli_2014). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of glycosylation at S81 (P = 0.0148);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at