ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.293+1del (rs777857395)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409817 SCV000485915 likely pathogenic Glycogen storage disease type III 2016-03-07 criteria provided, single submitter clinical testing
Invitae RCV000409817 SCV000827247 likely pathogenic Glycogen storage disease type III 2020-09-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the AGL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs777857395, ExAC no frequency). This variant has been reported in an individual affected with glycogen storage disease with the second AGL variant being unknown (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 370565). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409817 SCV001338160 likely pathogenic Glycogen storage disease type III 2020-02-14 criteria provided, single submitter clinical testing Variant summary: AGL c.293+1delG is 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 creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250334 control chromosomes (gnomAD). c.293+1delG has been reported in the literature in at least one individual affected with Glycogen Storage Disease Type III (Goldstein_2010). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001509044 SCV001715546 likely pathogenic not provided 2020-03-19 criteria provided, single submitter clinical testing PVS1, PM2
Natera, Inc. RCV000409817 SCV001454496 likely pathogenic Glycogen storage disease type III 2020-09-16 no assertion criteria provided clinical testing

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