Submissions for variant NM_000642.3(AGL):c.413G>A (p.Gly138Glu)

gnomAD frequency: 0.00001  dbSNP: rs773384152

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001067895	SCV001232978	uncertain significance	Glycogen storage disease type III	2022-05-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 138 of the AGL protein (p.Gly138Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 861380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect AGL function (PMID: 27088557). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282451	SCV002572014	uncertain significance	not specified	2022-08-13	criteria provided, single submitter	clinical testing	Variant summary: AGL c.413G>A (p.Gly138Glu) results in a non-conservative amino acid change located in the Glycogen debranching enzyme, glucanotransferase domain (IPR032792) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.413G>A has been reported in the literature without a second allele/genotype specification in individuals affected with Glycogen Storage Disease Type III (example, Goldstein_2010, Lu_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease Type III. At least one publication reports experimental evidence evaluating an impact on protein function (Zhai_2016). These results showed no damaging effect of this variant on enzyme specific activity as compared to wild-type when Candida glabrata glycogen debranching enzyme (CgGDE) is expressed in an E.Coli system. As Candida glabrata GDE reportedly has 38% sequence identity to human GDE, the exact relevance of this finding in-vivo is unclear. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001067895	SCV004049920	uncertain significance	Glycogen storage disease type III	2023-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001067895	SCV002091448	uncertain significance	Glycogen storage disease type III	2021-01-05	no assertion criteria provided	clinical testing