Submissions for variant NM_000030.3(AGXT):c.385G>C (p.Asp129His)

dbSNP: rs180177212

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186238	SCV000239562	uncertain significance	Primary hyperoxaluria, type I	2023-10-27	criteria provided, single submitter	clinical testing	PMID: 24718375 reported normal stability and activity in vitro. ACMG: PM2 PP3 BS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222437	SCV002500063	uncertain significance	not specified	2022-03-01	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.385G>C (p.Asp129His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 163230 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.0024), allowing no conclusion about variant significance. The variant, c.385G>C, has been reported in the literature to be found in at least one individual affected with Primary Hyperoxaluria Type 1, however no second variant was specified and no phenotype details were provided (Williams_2009); the variant was noted to be found on the major allele. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated wild-type activity and stability in a yeast growth assay, and normal expression and localization in COS-7 cells, however the variant was expressed on the minor allele (i.e. in cis with the polymorphic variant c.32C>T /P11L, which is less stable and has less activity than the major allele), and authors noted that (though unlikely) it cannot be excluded that this variant could show an effect in the context of the major allele (Lage_2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513966	SCV003518590	uncertain significance	not provided	2021-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with histidine at codon 129 of the AGXT protein (p.Asp129His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs180177212, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of primary hyperoxaluria, type 1 (PMID: 19479957). ClinVar contains an entry for this variant (Variation ID: 204034). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.