Submissions for variant NM_000030.3(AGXT):c.364C>T (p.Arg122Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177210

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818752	SCV000959382	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 204097). This premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 19479957, 21850686, 29244539). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg122*) in the AGXT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000186303	SCV001162773	pathogenic	Primary hyperoxaluria, type I	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type 1 (MIM#259900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical variability has been reported for affected relatives carrying the same pathogenic variant (GeneReviews, PMID: 35695965). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported as compound heterozygous in individuals with primary hyperoxaluria type 1 (ClinVar, PMIDs: 24385516, 30341509). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (external diagnostic report). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000186303	SCV001449177	pathogenic	Primary hyperoxaluria, type I	2021-04-08	criteria provided, single submitter	clinical testing	This individual is heterozygous for a pathogenic variant, c.364C>T in the AGXT gene. This variant creates a premature stop codon p.(Arg122*) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has been previously reported, homozygous or compound heterozygous with other AGXT disease causing variants, in individuals with hyperoxaluria (Dulz et al 2018 PMID: 29244539; Martinez-Turrillas et al 2019 PMID: 31715429; ClinVar, accessed: 20/07/21 https://www.ncbi.nlm.nih.gov/clinvar/variation/204097/). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 08/04/2021) with a very low allele frequency of 0.0006% (1 out of 159,126 alleles). This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PM3_Strong).
Revvity Omics, Revvity	RCV000186303	SCV002023837	pathogenic	Primary hyperoxaluria, type I	2023-05-15	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186303	SCV000239636	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research
Natera, Inc.	RCV000186303	SCV002076458	pathogenic	Primary hyperoxaluria, type I	2021-01-19	no assertion criteria provided	clinical testing