Submissions for variant NM_000030.3(AGXT):c.777-1G>C

gnomAD frequency: 0.00001  dbSNP: rs180177267

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169101	SCV000220293	likely pathogenic	Primary hyperoxaluria, type I	2014-05-01	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000169101	SCV000893591	pathogenic	Primary hyperoxaluria, type I	2022-01-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054661	SCV001219008	pathogenic	not provided	2023-08-25	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: 188774). Disruption of this splice site has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 15110324, 15963748, 17460142, 25629080). This variant is present in population databases (rs180177267, gnomAD 0.004%). This sequence change affects an acceptor splice site in intron 7 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	RCV001194150	SCV001363450	pathogenic	Primary hyperoxaluria	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.777-1G>C 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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes (gnomAD). The variant, c.777-1G>C, has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1 (Coulter-Mackie_2004, Coulter-Mackie_2005, Monico_2007, Williams_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication, Coulter-Mackie_2004, reports AGT activity of this variant from a patients liver biopsy was <10% of normal activity. One ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169101	SCV004194672	pathogenic	Primary hyperoxaluria, type I	2024-01-18	criteria provided, single submitter	clinical testing
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000169101	SCV000239721	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research
Natera, Inc.	RCV000169101	SCV001460163	pathogenic	Primary hyperoxaluria, type I	2020-09-16	no assertion criteria provided	clinical testing