Submissions for variant NM_000642.3(AGL):c.100C>T (p.Arg34Ter)

gnomAD frequency: 0.00001  dbSNP: rs781580050

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169056	SCV000220217	likely pathogenic	Glycogen storage disease type III	2014-04-04	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169056	SCV000918403	pathogenic	Glycogen storage disease type III	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: AGL c.100C>T (p.Arg34X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 246030 control chromosomes (gnomAD). The variant, c.100C>T, has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Glycogen Storage Disease Type III (Goldstein_2010, Horinishi_2002, Lu_2016, Lucchiari_2002, Wu_2013). These individuals also showed no AGL activity (Goldstein_2010, Lucchiari_2002). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169056	SCV000951932	pathogenic	Glycogen storage disease type III	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg34*) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This variant is present in population databases (rs781580050, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III (PMID: 11924557, 11977176, 24495762). ClinVar contains an entry for this variant (Variation ID: 188743). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000169056	SCV001424353	pathogenic	Glycogen storage disease type III		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169056	SCV002022986	pathogenic	Glycogen storage disease type III	2020-10-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169056	SCV002055461	pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000169056	SCV003841288	pathogenic	Glycogen storage disease type III	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000188743 / PMID: 11977176). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000169056	SCV004211235	pathogenic	Glycogen storage disease type III	2024-03-25	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000169056	SCV005329331	pathogenic	Glycogen storage disease type III	2023-05-20	criteria provided, single submitter	clinical testing	The stop-gained variant c.100C>T (p.Arg34Ter) in the AGL gene has been reported in the homozygous state in individuals affected with glycogen storage disease type III (Lu et al., 2016; Lucchiari et al., 2002). The variant has 0.002% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic (Multiple Submissions). This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV000169056	SCV002091423	pathogenic	Glycogen storage disease type III	2020-12-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745247	SCV005360383	pathogenic	AGL-related disorder	2024-09-09	no assertion criteria provided	clinical testing	The AGL c.100C>T variant is predicted to result in premature protein termination (p.Arg34*). This variant has been reported in the compound heterozygous and homozygous state in multiple individuals with glycogen storage disease type 3 (Lucchiari et al. 2002. PubMed ID: 11977176; Lu et al. 2016. PubMed ID: 26984562; Horinishi et al. 2002. PubMed ID: 11924557; Goldstein et al. 2010. PubMed ID: 20648714). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in AGL are expected to be pathogenic. This variant is interpreted as pathogenic.