Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002038576 | SCV002312696 | likely pathogenic | not provided | 2022-10-06 | 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 350 of the AGXT protein (p.Gly350Ser). This variant is present in population databases (rs199610919, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with AGXT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1520216). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly350 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9604803, 23551880, 30341509). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230727 | SCV003928673 | uncertain significance | not specified | 2023-04-04 | criteria provided, single submitter | clinical testing | Variant summary: AGXT c.1048G>A (p.Gly350Ser) 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. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 250450 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (8e-05 vs 0.0024), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1048G>A in individuals affected with Primary Hyperoxaluria Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Another missense variant at the same codon, Gly350Asp, has been classified as likely pathogenic/pathogenic in ClinVar indicating the glycine residue is critical for AGXT protein function. One ClinVar submitter (evaluation after 2014) cites this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV005017091 | SCV005651653 | uncertain significance | Primary hyperoxaluria, type I | 2024-05-24 | criteria provided, single submitter | clinical testing |