2-240869249-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000030.3(AGXT):c.245G>A(p.Gly82Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,588 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G82R) has been classified as Pathogenic.
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.245G>A | p.Gly82Glu | missense_variant | 2/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.245G>A | p.Gly82Glu | missense_variant | 2/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000472436.1 | n.265G>A | non_coding_transcript_exon_variant | 2/5 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251218Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135828
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461588Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727092
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 17, 2000 | - - |
Pathogenic, no assertion criteria provided | in vitro | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The AGXT c.245G>A variant has been reported in individual affected with Hyperoxaluria, primary, type 1 (Cellini et. al., 2007). Experimental studies have shown that this variant affects AGXT protein function (Lumb MJ & Danpure CJ., 2000; Cellini et. al., 2007). The p.Gly82Glu variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.001% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid change p.Gly82Glu in AGXT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant disrupts the p.Gly82 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (van woerden et. al., 2004). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 17, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 07, 2016 | - - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2023 | Variant summary: AGXT c.245G>A (p.Gly82Glu) 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 2e-05 in 251218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.245G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Primary Hyperoxaluria Type 1 (e.g., Purdue_1992, Coulter-Mackie_2001). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in less than ~2% of normal catalytic activity in both patient derived samples and in an in vitro expression system (e.g., Purdue_1992, Cellini_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17696873, 11708860, 1349575). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 82 of the AGXT protein (p.Gly82Glu). This variant is present in population databases (rs121908522, gnomAD 0.02%). This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 1349575). This variant is also known as G367A. ClinVar contains an entry for this variant (Variation ID: 5643). 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: 10960483, 17696873). This variant disrupts the p.Gly82 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15253729). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at