ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.32C>T (p.Pro11Leu) (rs34116584)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173049 SCV000224129 benign not specified 2014-09-24 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000173049 SCV000301569 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005995 SCV000429355 likely benign Primary hyperoxaluria, type I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000587789 SCV000693978 likely benign not provided 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The AGXT c.32C>T (p.Pro11Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/3 in silico tools. This variant was found in 17684/114424 control chromosomes (1706 homozygotes) (including ExAC) at a frequency of 0.154548, which is approximately 65 times the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717), thus this variant is common polymorphism. Available clinical and functional data show that this variant leads to synergistic effect with some common pathogenic variants (such as Gly170Arg and p.Ile244Thr) and presence of this variant in the same chromosome (in cis) with those pathogenic variants is required for their loss of function effect (Lumb_2000, Santana_2003, Van Woerden_2004, Lorenzo_2006, Monico_2007, Kanoun_2013). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign/likely benign. Taken together, primarily based on its role as a functional polymorphism and fact that its presence is required for determining pathogenicity of other mutations, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000173049 SCV001338182 likely benign not specified 2020-02-24 criteria provided, single submitter clinical testing Variant summary: AGXT c.32C>T (p.Pro11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.15 in 278214 control chromosomes, predominantly observed within the European (Finnish and non-Finnish) subpopulations (with a frequency of 0.2-0.24) in the gnomAD database, including 3886 homozygotes. The observed variant frequency within the European control individuals in the gnomAD database is approximately 80-100 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism. However, the variant, c.32C>T, has also been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1, together with two pathogenic variants (VanWoerden_2004, Lorenzo_2006, Kanoun_2013). Clinical and functional data show that this variant leads to a synergistic effect with some common pathogenic variants (e.g. Gly170Arg and p.Ile244Thr), and the presence of this variant in the same chromosome (in cis) is required for their loss of function effect (Lumb_2000, Santana_2003, Monico_2007). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign/likely benign. Based on the evidence outlined above, and primarily on its role as a functional polymorphism with a synergistic effect with pathogenic variants, the variant was classified as likely benign.
OMIM RCV000005995 SCV000026177 benign Primary hyperoxaluria, type I 2013-01-25 no assertion criteria provided literature only
GeneReviews RCV000005995 SCV000172447 benign Primary hyperoxaluria, type I 2014-07-17 no assertion criteria provided literature only
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000005995 SCV000239543 uncertain significance Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided in vitro

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