ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.2309-1G>A (rs786204481)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169136 SCV000220351 likely pathogenic Glycogen storage disease type III 2014-05-27 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587290 SCV000697530 pathogenic Glycogen storage disease IIIa 2017-08-13 criteria provided, single submitter clinical testing Variant summary: The c.2309-1G>A (aka IVS17-1G>A) in a AGL gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical acceptor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from control dataset of ExAC (~120120 chrs tested), but is present at a low frequency in gnomAD dataset (2/245384 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.00228. The variant has been reported in affected individuals with enzymatically confirmed dx of GSDIII via publications and is cited as Likely Pathogenic by a reputable database/clinical laboratory. Taken together, the variant was classified as Pathogenic.
Invitae RCV000169136 SCV001575138 likely pathogenic Glycogen storage disease type III 2020-08-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the AGL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glycogen storage disease (PMID: 20648714, 27460348). ClinVar contains an entry for this variant (Variation ID: 188804). 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.

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