Submissions for variant NM_000030.3(AGXT):c.823_824dup (p.Ser275fs)

dbSNP: rs180177273

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780823	SCV000918406	pathogenic	Primary hyperoxaluria	2018-11-30	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.823_824dupAG (p.Ser275ArgfsX38) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 246216 control chromosomes (gnomAD). c.823_824dupAG has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (Chen_2015, Cui_2017, Li_2014, Yuen_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209339	SCV001380769	pathogenic	not provided	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser275Argfs*38) 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). This variant is present in population databases (rs747071948, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 26252291, 30541997). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.824_825insAG and c.815_816insGA. ClinVar contains an entry for this variant (Variation ID: 204201). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000186408	SCV004194583	pathogenic	Primary hyperoxaluria, type I	2024-03-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000186408	SCV005086813	pathogenic	Primary hyperoxaluria, type I	2023-07-17	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, with intrafamilial variability reported (GeneReviews). (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) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in both compound heterozygous and homozygous individuals with primary hyperoxaluria, bilateral stones and a UTI. Two of these individuals also had haematuria (PMID: 37139236, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000186408	SCV005651635	pathogenic	Primary hyperoxaluria, type I	2024-05-17	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186408	SCV000239758	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research
Natera, Inc.	RCV000186408	SCV002076478	pathogenic	Primary hyperoxaluria, type I	2020-10-19	no assertion criteria provided	clinical testing
Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University	RCV000186408	SCV005368648	pathogenic	Primary hyperoxaluria, type I	2024-08-26	no assertion criteria provided	clinical testing	Variant_type:truncating/MutationTaster:NONE/CADD:NONE/phyloP:NONE/phastCons:NONE/gnomAD_exome_EastAsian:NONE/ExAC_EastAsian:NONE/dbSNP:NONE