Submissions for variant NM_000030.3(AGXT):c.846+1G>T

gnomAD frequency: 0.00001  dbSNP: rs180177281

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000806714	SCV000946728	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 204159). This variant is also known as IVS8+1G>T. Disruption of this splice site has been observed in individuals with primary hyperoxaluria type 1 (PMID: 15110324, 25296721, 25629080). This variant is present in population databases (rs180177281, gnomAD 0.003%). This sequence change affects a donor splice site in intron 8 of the AGXT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307438	SCV002600384	pathogenic	Primary hyperoxaluria	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.846+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251086 control chromosomes (gnomAD). c.846+1G>T has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Primary Hyperoxaluria Type 1 (e.g. Coulter-Mackie_2004, Monico_2007, Williams_2015). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000186366	SCV004194850	pathogenic	Primary hyperoxaluria, type I	2023-06-06	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186366	SCV000239713	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research
Natera, Inc.	RCV000186366	SCV002076480	pathogenic	Primary hyperoxaluria, type I	2021-01-11	no assertion criteria provided	clinical testing