ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.2681+1G>A (rs201201443)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724650 SCV000331829 pathogenic not provided 2016-07-11 criteria provided, single submitter clinical testing
Invitae RCV000377764 SCV000626705 pathogenic Glycogen storage disease type III 2020-09-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 20 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 (rs201201443, ExAC 0.006%). This variant has been observed in several individuals affected with glycogen storage disease (PMID: 10472540, 16705713). ClinVar contains an entry for this variant (Variation ID: 281229). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 10472540). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000377764 SCV001338430 pathogenic Glycogen storage disease type III 2020-04-24 criteria provided, single submitter clinical testing Variant summary: AGL c.2681+1G>A 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 abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in exon 21 skipping (Hadjigeorgiou_AGL_JIMD_1999). The variant allele was found at a frequency of 3.2e-05 in 251020 control chromosomes (gnomAD). c.2681+1G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III (Hadjigeorgiou_1999, Lucchiari_2007). These data indicate that the variant is very likely to be associated with disease. AGL activity and protein were found to be almost absent in patients muscle specimens (Hadjigeorgiou_1999). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000377764 SCV001132327 pathogenic Glycogen storage disease type III 2014-01-02 no assertion criteria provided clinical testing

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