Submissions for variant NM_000030.3(AGXT):c.847-1G>C

dbSNP: rs180177285

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000186375	SCV000793210	likely pathogenic	Primary hyperoxaluria, type I	2017-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269136	SCV001448395	pathogenic	Primary hyperoxaluria	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: AGXT c.847-1G>C alters a conserved nucleotide 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 a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 151426 control chromosomes. c.847-1G>C has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 and subsequently cited by others (example, Basmaison_2000, Fargue_2009, Coulter-Mackie_2004, Pirulli_2003, Williams_2009, Mandrile_2014). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000186375	SCV004194817	pathogenic	Primary hyperoxaluria, type I	2024-03-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000186375	SCV005086815	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. Clinical variability has been reported for affected relatives carrying the same pathogenic variant (PMIDs: 20301460, 35695965). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice site variants comparable to the one identified in this case have strong previous evidence for pathogenicity. c.847-3C>G and c.847-2_847-1del have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar, and c.847-1G>A has been observed as homozygous in an individual with primary hyperoxaluria (PMID: 25629080). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar and has been observed as homozygous or compound heterozygous in individuals with primary hyperoxaluria (PMIDs: 35812297, 23940605, 19571789, 10862087). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186375	SCV000239723	pathogenic	Primary hyperoxaluria, type I	2014-11-27	no assertion criteria provided	research