ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.4260-12A>G (rs369973784)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020379 SCV000220759 likely pathogenic Glycogen storage disease type III 2014-09-30 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000675344 SCV000229533 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Invitae RCV000020379 SCV000626749 pathogenic Glycogen storage disease type III 2020-10-26 criteria provided, single submitter clinical testing This sequence change falls in intron 31 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369973784, ExAC 0.03%). This variant has been reported to segregate with glycogen storage disease type III (GSDIII) in several large families (PMID: 9490286, 25827695) and and has been observed in multiple unrelated individuals affected with GSDIII (PMID: 10655153, 11924557, 20648714, 22089644, 23430490). This variant is also known as IVS32-12A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 1099). Studies have shown that this variant is associated with an 11 nucleotide insertion, which introduces a frameshift (PMID:9490286). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000020379 SCV001162837 pathogenic Glycogen storage disease type III criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020379 SCV001362038 pathogenic Glycogen storage disease type III 2019-10-31 criteria provided, single submitter clinical testing Variant summary: AGL c.4260-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 acceptor site. Three predict the variant creates a cryptic 3 acceptor site. At least two publication reports this variant created a new 3' splice site and resulted in insertion of an 11-bp intron sequence between exon 32 and exon 33 in the patients debrancher mRNA. The predicted mutant enzyme was truncated by 112 amino acids as a result of premature termination (p.Phe1420Hisfs*16) (Okubo_1998, Shaiu_2000). The variant allele was found at a frequency of 5.8e-05 in 243346 control chromosomes (gnomAD). c.4260-12A>G has been reported in the literature in multiple individuals in compound heterozygous or homozygous states affected with Glycogen Storage Disease Type III (Okubo_1998, Shaiu_2000, Lu_2016, Sentner_2012). These data indicate that the variant is very likely to be associated with disease. At least two publication reports this variant had an impact on protein function and debrancher activity in a liver specimen was reduced to less than 30% of the control value (Okubo_1998, Shaiu_2000). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Nilou-Genome Lab RCV000020379 SCV001623484 likely pathogenic Glycogen storage disease type III 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000001157 SCV000021307 pathogenic Glycogen storage disease IIIb 2000-01-01 no assertion criteria provided literature only
OMIM RCV000001158 SCV000021308 pathogenic Glycogen storage disease IIIa 2000-01-01 no assertion criteria provided literature only
GeneReviews RCV000020379 SCV000055699 pathologic Glycogen storage disease type III 2012-09-06 no assertion criteria provided curation Converted during submission to Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000675344 SCV000801010 pathogenic not provided 2018-01-09 no assertion criteria provided clinical testing

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