ClinVar Miner

Submissions for variant NM_000030.3(AGXT):c.33dup (p.Lys12fs) (rs180177201)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute RCV000128800 SCV000786702 pathogenic Primary hyperoxaluria, type I criteria provided, single submitter research The homozgous c.33dupC variant was identified by our study in one individual with Hyperoxaluria. The c.33dupC is a well-established known pathogenic variant (https://www.ncbi.nlm.nih.gov/books/NBK1283/) and loss of function is a known mechanism of disease in the AGXT gene.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000128800 SCV000891673 pathogenic Primary hyperoxaluria, type I 2017-12-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779688 SCV000916432 pathogenic Primary hyperoxaluria 2018-09-24 criteria provided, single submitter clinical testing Variant summary: AGXT c.33dupC (p.Lys12GlnfsX156) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 30572 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00047 vs 0.0024), allowing no conclusion about variant significance. c.33dupC has been reported in the literature in a multiple affected individuals with Primary Hyperoxaluria Type 1 (Rumsby_2004, Mbarek_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Rumsby 2004). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000800941 SCV000940686 pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys12Glnfs*156) in the AGXT gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This is one of the most common variants reported in individuals affected with primary hyperoxaluria (PMID: 15327387, 19479957, 25629080, 27135212). It is also known as 33_34insC in the literature. ClinVar contains an entry for this variant (Variation ID: 140583). Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000128800 SCV001136271 pathogenic Primary hyperoxaluria, type I 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000128800 SCV001194104 pathogenic Primary hyperoxaluria, type I 2019-12-20 criteria provided, single submitter clinical testing NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 17495019. Classification of NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
GeneDx RCV000800941 SCV001765015 pathogenic not provided 2020-02-26 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32556641, 31980526, 15110324, 31102713, 29127259, 29456205, 30655312, 30341509, 28619084, 10453743, 20549407, 16931222, 27135212, 28969594)
GeneReviews RCV000128800 SCV000172449 pathogenic Primary hyperoxaluria, type I 2014-07-17 no assertion criteria provided literature only
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000128800 SCV000239730 pathogenic Primary hyperoxaluria, type I 2014-11-27 no assertion criteria provided research
Natera, Inc. RCV000128800 SCV001456043 pathogenic Primary hyperoxaluria, type I 2020-09-16 no assertion criteria provided clinical testing

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