Submissions for variant NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter)

gnomAD frequency: 0.00011  dbSNP: rs12118058

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531434	SCV000626760	pathogenic	Glycogen storage disease type III	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1487*) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the AGL protein. This variant is present in population databases (rs12118058, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type III (PMID: 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). This variant disrupts a region of the AGL protein in which other variant(s) (p.Tyr1510*) have been determined to be pathogenic (PMID: 8990006, 20071996, 20490926, 23430490). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000531434	SCV000793936	likely pathogenic	Glycogen storage disease type III	2017-09-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825508	SCV000966816	likely pathogenic	Glycogen storage disease	2018-01-10	criteria provided, single submitter	clinical testing	The p.Arg1487X variant in AGL has been reported in the compound heterozygous sta te in 1 individual with glycogen storage disorder type III (GSDIII; Quackenbush 2016). It has also been identified in 2/24018 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12118058 ), which is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1487. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated p rotein. Many other truncating variants, which are also predicted to escape NMD a nd located in this region of the AGL gene, have been reported in affected indivi duals with deficient enzyme activity, suggesting that the carboxy terminus is es sential for normal enzyme function (Parvari 1997, Shen 1997, Rousseau-Nepton 201 5, Lu 2016). In summary, although additional studies are required to fully estab lish its clinical significance, the p.Arg1487X variant is likely pathogenic. ACM G/AMP Criteria applied: PVS1_Strong, PM3, PP4.
Revvity Omics, Revvity	RCV000531434	SCV002023703	pathogenic	Glycogen storage disease type III	2023-05-23	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000531434	SCV002055551	likely pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000531434	SCV002500079	pathogenic	Glycogen storage disease type III	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: AGL c.4459C>T (p.Arg1487X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. This variant is not anticipated to result in nonsense mediated decay, however variants downstream from this position have been classified pathogenic internally or in ClinVar (CV IDS:1094, 656738). The variant allele was found at a frequency of 3.6e-05 in 250906 control chromosomes (gnomAD). c.4459C>T has been reported in the literature in a compound heterozygous individual affected with Glycogen Storage Disease (example: Quackenbush_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31980526, 17994282, 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000531434	SCV004214542	pathogenic	Glycogen storage disease type III	2024-03-16	criteria provided, single submitter	clinical testing