ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.4221dup (p.Leu1408fs) (rs786204655)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169447 SCV000220867 likely pathogenic Glycogen storage disease type III 2014-11-07 criteria provided, single submitter literature only
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000169447 SCV000845640 pathogenic Glycogen storage disease type III 2018-08-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169447 SCV001363063 pathogenic Glycogen storage disease type III 2021-02-21 criteria provided, single submitter clinical testing Variant summary: AGL c.4221dupA (p.Leu1408IlefsX14) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251128 control chromosomes. c.4221dupA has been reported in the literature in at-least one individual affected with Glycogen Storage Disease Type III and subsequently cited by others (example, Pavari_1998, Fukuda_2000). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of normal leukocyte debrancher enzyme activity in a sample obtained from a patient who was compound heterozygous for this variant and another frameshifting mutation in the AGL gene (Pavari_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic with one citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169447 SCV001411247 pathogenic Glycogen storage disease type III 2019-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1408Ilefs*14) in the AGL 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 variant has been observed in individual(s) with glycogen storage disease (PMID: 9584265). ClinVar contains an entry for this variant (Variation ID: 189052). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.

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