Submissions for variant NM_000030.3(AGXT):c.806T>C (p.Leu269Pro)

dbSNP: rs180177271

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186334	SCV000239680	pathogenic	Primary hyperoxaluria, type I	2023-10-27	criteria provided, single submitter	clinical testing	Reduced AGT activity in vitro (PMID:24718375). ACMG: PS3 PM2 PM3 PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852425	SCV002168482	likely pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects AGXT function (PMID: 24718375). 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. ClinVar contains an entry for this variant (Variation ID: 204128). This missense change has been observed in individual(s) with clinical features of primary hyperoxaluria (PMID: 19479957; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 269 of the AGXT protein (p.Leu269Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282021	SCV002571940	uncertain significance	not specified	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.806T>C (p.Leu269Pro) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes (gnomAD). c.806T>C has been reported in the literature in at least one individual presumably affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009). This report does not provide unequivocal conclusions about association of the variant with Primary Hyperoxaluria Type 1. One publication reports experimental evidence evaluating an impact on protein function. The variant protein was found to have <5% of normal activity and stability with both the minor and major alleles of AGXT in a yeast cell-based assay system (e.g. Lage_2014). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic, until additional evidence of clinical and/or functional importance becomes available.