ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.32C>G (p.Pro11Arg)

dbSNP: rs34116584
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000186275 SCV001162942 likely pathogenic Primary hyperoxaluria, type I criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553704 SCV001774677 likely pathogenic Primary hyperoxaluria 2021-07-22 criteria provided, single submitter clinical testing 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 homozygote. This frequency is not significantly higher than expected 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). 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). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001857587 SCV002232412 pathogenic not provided 2021-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the AGXT protein (p.Pro11Arg). This variant is present in population databases (rs34116584, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary hyperoxaluria (PMID: 22821680, 32556641). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 204069). 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. Experimental studies have shown that this missense change affects AGXT function (PMID: 22821680). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001857587 SCV002513151 likely pathogenic not provided 2021-11-02 criteria provided, single submitter clinical testing Published functional studies demonstrate showed that p.(P11R) reduced the enzymatic activity to about 31% of the wild-type (Tammachote et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32102150, 19479957, 31589614, 30341509, 32792227, 28904440, 33691640, 22821680, 32556641, 33721035)
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000186275 SCV000239600 pathogenic Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided in vitro
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000186275 SCV001469157 pathogenic Primary hyperoxaluria, type I 2020-11-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000186275 SCV002076450 likely pathogenic Primary hyperoxaluria, type I 2020-04-04 no assertion criteria provided clinical testing

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