ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.4459C>T (p.Arg1487Ter) (rs12118058)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000531434 SCV000626760 pathogenic Glycogen storage disease type III 2020-10-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the AGL gene (p.Arg1487*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acids of the AGL protein. This variant is present in population databases (rs12118058, ExAC 0.02%). This variant has been observed in an individual affected with glycogen storage disease type III (PMID: 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). A different truncation (p.Tyr1510*) that lies downstream of this variant has been determined to be pathogenic (PMID: 8990006, 23430490, 20071996, 20490926). This suggests that deletion of this region of the AGL protein is causative of disease. 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
Illumina Clinical Services Laboratory,Illumina RCV000531434 SCV000914339 uncertain significance Glycogen storage disease type III 2018-12-06 criteria provided, single submitter clinical testing The AGL c.4459C>T (p.Arg1487Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. This variant is located in the last 50 bp of the penultimate exon and may escape nonsense-mediated decay. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare 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,; 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.

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