ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.777-1G>C (rs180177267)

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Total submissions: 6
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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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001054661 SCV001219008 pathogenic not provided 2020-04-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the AGXT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs180177267, ExAC 0.003%). This variant has been observed in combination with another AGXT variant in several individuals affected with primary hyperoxaluria type 1 (PMID: 25629080, 17460142, 15110324, 15963748 ). ClinVar contains an entry for this variant (Variation ID: 188774). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). For these reasons, this variant has been classified as Pathogenic.
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.
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

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