Submissions for variant NM_000642.3(AGL):c.664+3A>G

gnomAD frequency: 0.00001  dbSNP: rs370792293

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169374	SCV000220754	likely pathogenic	Glycogen storage disease type III	2014-09-30	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585987	SCV000697535	pathogenic	Glycogen storage disease IIIa	2017-04-21	criteria provided, single submitter	clinical testing	Variant summary: The AGL c.664+3A>G variant is an intronic change that involves a conserved nucleotide. 3/5 splice prediction tools predict an impact on normal splicing, which was confirmed by Lucchiar_2002. The cDNA analysis revealed found an in-frame deletion of exon 6 caused by the variant of interest, and, as confirmation, all homozygous patients showed no enzymatic residual activity. This variant was found in 2/120192 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822). The variant was identified in multiple GSD III patients homozygously or in compound heterozygosity. Lastly, a clinical diagnostic laboratory classifies the variant as "likely pathogenic." Taking together, the variant of interest has been classified as "pathogenic."
Invitae	RCV000169374	SCV001382430	pathogenic	Glycogen storage disease type III	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 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 likely results in a shortened protein product. This variant is present in population databases (rs370792293, gnomAD 0.002%). This variant has been observed in individual(s) with glycogen storage disease type III (PMID: 12442284, 16705713, 21691223). This variant is also known as IVS6 +3 A>G. ClinVar contains an entry for this variant (Variation ID: 188994). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 (also known as exon 6), but is expected to preserve the integrity of the reading-frame (PMID: 12442284). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169374	SCV002055470	likely pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000169374	SCV004171066	pathogenic	Glycogen storage disease type III	2023-11-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169374	SCV004211046	pathogenic	Glycogen storage disease type III	2024-02-14	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000169374	SCV000536700	likely pathogenic	Glycogen storage disease type III	2014-10-31	no assertion criteria provided	research
Natera, Inc.	RCV000169374	SCV001454498	pathogenic	Glycogen storage disease type III	2020-09-16	no assertion criteria provided	clinical testing