ClinVar

Description

Variant summary: AGXT c.32C>G (p.Pro11Arg) 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 0.00016 in 246986 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00016 vs 0.0024), allowing no conclusion about variant significance. c.32C>G has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (e.g. Williams_2009, Tammachote_2012, Krishnamurthy_2017, Zhao_2020, Lin_2021, Saha_2023). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact on protein function and results in reduced the enzymatic activity (Williams_2009, Tammachote_2012). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.