Submissions for variant NM_000030.3(AGXT):c.481G>A (p.Gly161Ser)

dbSNP: rs180177227

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001069631	SCV001234810	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the AGXT protein (p.Gly161Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 17460142, 25629080, 28893421). ClinVar contains an entry for this variant (Variation ID: 204105). 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 not expected to disrupt AGXT protein function. Experimental studies have shown that this missense change affects AGXT function (PMID: 24055001). This variant disrupts the p.Gly161 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25629080; Invitae). 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	RCV003226241	SCV003922510	pathogenic	Primary hyperoxaluria	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.481G>A (p.Gly161Ser) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Three variants, namely p.Gly161Arg/Ser/Cys affecting this residue have been reported among PH1 patients: p.G161R on the major allele and p.G161S and p.G161C on the minor allele. These mutations are predicted to interfere with AGT folding promoting protein aggregation (reviewed in Mandrile_2023). 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 1.8e-05 in 226372 control chromosomes. c.481G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Primary Hyperoxaluria Type 1 (example, Daga_2018, Williams_2015). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000186311	SCV004192750	pathogenic	Primary hyperoxaluria, type I	2023-03-22	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186311	SCV000239647	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	in vitro
Yale Center for Mendelian Genomics, Yale University	RCV000662317	SCV000784649	likely pathogenic	Nephrocalcinosis; Nephrolithiasis	2017-09-08	no assertion criteria provided	literature only
Natera, Inc.	RCV000186311	SCV002076461	pathogenic	Primary hyperoxaluria, type I	2020-08-12	no assertion criteria provided	clinical testing