Submissions for variant NM_000642.3(AGL):c.753_756del (p.Asp251fs)

dbSNP: rs748789700

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409582	SCV000485852	pathogenic	Glycogen storage disease type III	2016-02-26	criteria provided, single submitter	clinical testing
Invitae	RCV000409582	SCV000626766	pathogenic	Glycogen storage disease type III	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp251Glufs*23) 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 (rs748789700, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III with or without cardiomyopathy (PMID: 16189622, 16705713, 23430490, 25431232). ClinVar contains an entry for this variant (Variation ID: 370509). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409582	SCV000918404	pathogenic	Glycogen storage disease type III	2018-08-09	criteria provided, single submitter	clinical testing	Variant summary: AGL c.753_756delCAGA (p.Asp251GlufsX23) 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 (eg. c.2039G>A, p.Trp680X; c.2929C>T, p.Arg977X, c.3216_3217delGA, p.Glu1072fsX36). The variant allele was found at a frequency of 2.9e-05 in 277370 control chromosomes (gnomAD and publications). The variant, c.753_756delCAGA, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III in both homozygous and compound heterozygous form (Sentner_2012, Okubo_2011, Endo_2005, Li_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sentner_2012, Li_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001008814	SCV001168615	pathogenic	not provided	2019-03-21	criteria provided, single submitter	clinical testing	The c.753_756delCAGA variant (also reported as 750_753delAGA, due to alternate nomenclature) in the AGL gene has been reported previously in the homozygous state in individuals with glycogen storage disease type III (Endo et al., 2005; Sentner et al., 2012; Sentner et al., 2013). The c.753_756delCAGA variant causes a frameshift starting with codon Aspartic acid 251, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Asp251GlufsX23. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.753_756delCAGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.753_756delCAGA as a pathogenic variant.
Centogene AG - the Rare Disease Company	RCV000409582	SCV001424356	pathogenic	Glycogen storage disease type III		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000409582	SCV002023008	pathogenic	Glycogen storage disease type III	2019-12-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000409582	SCV002055471	pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
3billion	RCV000409582	SCV002318736	pathogenic	Glycogen storage disease type III	2022-03-22	criteria provided, single submitter	clinical testing	Frameshift: 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/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000370509, PMID:16189622). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000357). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000409582	SCV002812641	pathogenic	Glycogen storage disease type III	2021-12-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409582	SCV004211179	pathogenic	Glycogen storage disease type III	2023-08-11	criteria provided, single submitter	clinical testing
Centre for Human Genetics	RCV000409582	SCV001976629	pathogenic	Glycogen storage disease type III	2021-08-10	no assertion criteria provided	clinical testing	disease causing
Natera, Inc.	RCV000409582	SCV002091454	pathogenic	Glycogen storage disease type III	2020-09-12	no assertion criteria provided	clinical testing