Submissions for variant NM_000030.3(AGXT):c.245G>A (p.Gly82Glu)

gnomAD frequency: 0.00002  dbSNP: rs121908522

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000005997	SCV000485912	likely pathogenic	Primary hyperoxaluria, type I	2016-03-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851685	SCV002233889	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234894	SCV003933841	pathogenic	Primary hyperoxaluria	2023-05-10	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000005997	SCV004047613	pathogenic	Primary hyperoxaluria, type I		criteria provided, single submitter	clinical testing	The observed missense variant c.245G>A (p.Gly82Glu) in gene has been reported in homozygous and compound heterozygous state individuals affected with Hyperoxaluria, primary (Milliner DS et al. 2022; Coulter-Mackie MB et al. 2001). Experimental studies have shown that this missense change affects AGXT function (Cellini B et al. 2007). The p.Gly82Glu variant has allele frequency 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid change p.Gly82Glu in AGXT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 82 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000005997	SCV004194572	pathogenic	Primary hyperoxaluria, type I	2023-12-15	criteria provided, single submitter	clinical testing
OMIM	RCV000005997	SCV000026179	pathogenic	Primary hyperoxaluria, type I	2000-11-17	no assertion criteria provided	literature only
GeneReviews	RCV000005997	SCV000172451	not provided	Primary hyperoxaluria, type I		no assertion provided	literature only
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000005997	SCV000239620	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	in vitro
Yale Center for Mendelian Genomics, Yale University	RCV000005997	SCV002106577	pathogenic	Primary hyperoxaluria, type I	2019-01-17	no assertion criteria provided	literature only