Submissions for variant NM_000642.3(AGL):c.4322_4323dup (p.Gly1442fs)

dbSNP: rs1057516994

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409602	SCV000486559	likely pathogenic	Glycogen storage disease type III	2016-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000481572	SCV000568794	pathogenic	not provided	2016-11-23	criteria provided, single submitter	clinical testing	The c.4322_4323dupAA pathogenic variant in the AGL gene has been reported previously using alternate nomenclature (c.4323_4324insAA or c.4724insAA), either in the homozygous state or in combination with another AGL variant, in several individuals with a diagnosis of glycogen storage disease type III confirmed by enzyme analysis (Decostre et al., 2016; Lucchiari et al., 2002). The c.4322_4323dupAA variant causes a frameshift starting with codon Glycine 1442, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Gly1442LysfsX28. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.4322_4323dupAA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4322_4323dupAA as a pathogenic variant.
Genome-Nilou Lab	RCV000409602	SCV002055511	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	RCV000409602	SCV002598667	pathogenic	Glycogen storage disease type III	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: AGL c.4322_4323dupAA (p.Gly1442LysfsX28) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250644 control chromosomes (gnomAD). c.4322_4323dupAA has been reported in the literature in individuals affected with Glycogen Storage Disease Type III (examples: Laforet_2019 and Decostre_2017). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409602	SCV005834136	pathogenic	Glycogen storage disease type III	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1442Lysfs*28) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease III (PMID: 28888851, 31661040). This variant is also known as c.4323_4324insAA. ClinVar contains an entry for this variant (Variation ID: 371085). For these reasons, this variant has been classified as Pathogenic.