Submissions for variant NM_000642.3(AGL):c.18_19del (p.Gln6fs)

dbSNP: rs113994127

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723819	SCV000227163	pathogenic	not provided	2014-06-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000175637	SCV000346051	likely pathogenic	Glycogen storage disease type III	2017-04-27	criteria provided, single submitter	clinical testing	The AGL c.18_19delGA (p.Gln6HisfsTer20) variant, also referred to as c.17_18delAG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Gln6HisfsTer20 variant has been reported in at least three studies in which it is found in a total of 17 patients with glycogen storage disease type III, including in one in a homozygous state, in three in a compound heterozygous state, and in 13 in a heterozygous state where a second variant was not identified (Shen et al. 1996; Goldstein et al. 2010; Hobson-Webb et al. 2010). The p.Gln6HisfsTer20 variant was absent from 20 controls, but is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Gln6HisfsTer20 variant is classified as likely pathogenic for glycogen storage disease type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001155	SCV000697529	pathogenic	Glycogen storage disease IIIb	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The AGL c.18_19delGA (p.Gln6Hisfs) variant results in a premature termination codon, predicted to cause a truncated or absent AGL 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 (e.g. c.3216_3217delGA/p.Glu1072fs). This variant is absent from 121356 control chromosomes (ExAC dataset). This variant has been reported homozygously and in compound heterozygosity in patients with clinically and biochemically confirmed dx of GSD IIIb (Goldstein_GeneticsMed_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic". Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000175637	SCV000939193	pathogenic	Glycogen storage disease type III	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln6Hisfs*20) 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 (rs113994127, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with glycogen storage disease III (PMID: 8755644, 20490926, 20648714). ClinVar contains an entry for this variant (Variation ID: 195097). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000175637	SCV001194065	likely pathogenic	Glycogen storage disease type III	2019-12-04	criteria provided, single submitter	clinical testing	NM_000642.2(AGL):c.18_19delGA(Q6Hfs*20) is classified as likely pathogenic in the context of glycogen storage disease type III. Sources cited for classification include the following: PMID 20648714 and 8755644. Classification of NM_000642.2(AGL):c.18_19delGA(Q6Hfs*20) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000175637	SCV001448994	pathogenic	Glycogen storage disease type III	2017-09-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000175637	SCV002055456	pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000723819	SCV003761773	pathogenic	not provided	2021-02-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34820282, 20648714, 30487145, 20301788, 20526204, 20490926, 20071996, 8755644, 31263214, 32222031, 33368379, 31589614)
Baylor Genetics	RCV000175637	SCV004214387	pathogenic	Glycogen storage disease type III	2024-03-30	criteria provided, single submitter	clinical testing
OMIM	RCV000001155	SCV000021305	pathogenic	Glycogen storage disease IIIb	1996-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000175637	SCV000040762	not provided	Glycogen storage disease type III		no assertion provided	literature only	Associated with GSD IIIb phenotype
Natera, Inc.	RCV000175637	SCV001454492	pathogenic	Glycogen storage disease type III	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745253	SCV005350570	pathogenic	AGL-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The AGL c.18_19delGA variant is predicted to result in a frameshift and premature protein termination (p.Gln6Hisfs*20). This sequence variant has been reported to be one of the most common causative variants for glycogen storage disease (GSD) type IIIb (Shen et al. 1996. PubMed ID: 8755644; Goldstein et al. 2010. PubMed ID: 20648714). This variant has also been described in the literature as 17del and c.17_18del. This variant is interpreted as pathogenic.