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

gnomAD frequency: 0.00006  dbSNP: rs369973784

Total submissions: 16

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
Invitae	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		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 condition	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
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