ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.2590C>T (p.Arg864Ter) (rs113994130)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723818 SCV000227632 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020376 SCV000916426 pathogenic Glycogen storage disease type III 2018-08-16 criteria provided, single submitter clinical testing Variant summary: AGL c.2590C>T (p.Arg864X) 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 7.2e-05 in 276720 control chromosomes (gnomAD). c.2590C>T has been widely reported in the literature as pathogenic, found in numerous individuals affected with Glycogen Storage Disease Type III, across several ethnicities (e.g. Endo 2006, Mili 2012, Okubo 2015, Zhang 2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, by measuring leukocyte enzyme activities in several homozygous patients. The most pronounced variant effect results in <10% of normal activity (Mili 2012, Okubo 2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000020376 SCV000938468 pathogenic Glycogen storage disease type III 2020-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg864*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs113994130, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with glycogen storage disease type III (PMID: 87556440) and has also been observed in multiple individuals affected with glycogen storage disease type III (PMID: 12955720, 25451950, 20648714, 17047887). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 21215). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020376 SCV000040764 pathologic Glycogen storage disease type III 2012-09-06 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000020376 SCV001456534 pathogenic Glycogen storage disease type III 2020-09-16 no assertion criteria provided clinical testing

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