ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs369973784
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Total submissions: 17
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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
Eurofins Ntd Llc (ga) RCV000675344 SCV000229533 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000020379 SCV000626749 pathogenic Glycogen storage disease type III 2024-01-20 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, gnomAD 0.02%). This variant has been observed in individuals with glycogen storage disease type III (GSDIII) (PMID: 9490286, 10655153, 11924557, 20648714, 22089644, 23430490, 25827695). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS32-12A>G. ClinVar contains an entry for this variant (Variation ID: 1099). Studies have shown that this variant results in 11 nucleotide insertion and introduces a premature termination codon (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 2024-03-14 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.
Genome-Nilou Lab RCV000020379 SCV001623484 likely pathogenic Glycogen storage disease type III 2021-05-18 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000020379 SCV002556779 pathogenic Glycogen storage disease type III 2021-07-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000020379 SCV002778005 pathogenic Glycogen storage disease type III 2022-01-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407251 SCV004109165 pathogenic AGL-related disorder 2023-02-10 criteria provided, single submitter clinical testing The AGL c.4260-12A>G variant is predicted to interfere with splicing. This variant has been reported, homozygous, in four families with multiple affected individuals with glycogen storage disease type 3 (GSD III). Haplotype analysis showed that this variant is a founder mutation in Saudia Arabia and cDNA sequence analysis showed that it leads to a truncated protein (Basit et al. 2014. PubMed ID: 25827695). It’s also been reported in the homozygous and compound heterozygous state in multiple unrelated patients, including one patient who showed excessive accumulation of glycogen in the liver (Okubo et al. 1998. PubMed ID: 9490286, Hijazi et al. 2021. PubMed ID: 34820282, Table S1 - Fang et al. 2021. PubMed ID: 33763395). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-100381954-A-G). This variant is interpreted as pathogenic.
GeneDx RCV000675344 SCV004168970 likely pathogenic not provided 2023-04-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Okubo et al., 1998); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9490286, 33763395, 31589614, 34820282, 25827695)
Revvity Omics, Revvity RCV000020379 SCV004235534 pathogenic Glycogen storage disease type III 2023-06-21 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000020379 SCV004805787 pathogenic Glycogen storage disease type III 2024-03-29 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 not provided Glycogen storage disease type III no assertion provided literature only Associated with milder phenotype
Mayo Clinic Laboratories, Mayo Clinic RCV000675344 SCV000801010 pathogenic not provided 2018-01-09 no assertion criteria provided clinical testing
Natera, Inc. RCV000020379 SCV002094577 pathogenic Glycogen storage disease type III 2020-07-20 no assertion criteria provided clinical testing

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