Submissions for variant NM_000642.3(AGL):c.2023C>T (p.Arg675Trp)

gnomAD frequency: 0.00001  dbSNP: rs765749454

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778176	SCV000914335	uncertain significance	Glycogen storage disease type III	2017-06-26	criteria provided, single submitter	clinical testing	The AGL c.2023C>T (p.Arg675Trp) missense variant has been reported in two studies in which it is found in a compound heterozygous state with a nonsense variant on the second allele in two unrelated patients with glycogen storage disease type III (GSD III) (Lucchiari et al. 2002; Ko et al. 2014). The p.Arg675Trp variant was absent from 120 control chromosomes (Lucchiari et al. 2002) and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. The patient included in Lucchiari et al. (2014) study had no residual AGL activity. An in vitro enzyme activity assay using AGL from Candida glabrata showed that the Arg675Trp substitution only partially affected enzyme activity compared to wild type (Zhai et al. 2016). Based on the evidence, the p.Arg675Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000778176	SCV003295037	uncertain significance	Glycogen storage disease type III	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 675 of the AGL protein (p.Arg675Trp). This variant is present in population databases (rs765749454, gnomAD 0.002%). This missense change has been observed in individuals with AGL-related conditions (PMID: 12442284, 24257475). ClinVar contains an entry for this variant (Variation ID: 631558). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AGL protein function with a negative predictive value of 80%. 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.
Genome-Nilou Lab	RCV000778176	SCV004049986	uncertain significance	Glycogen storage disease type III	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000778176	SCV004214398	likely pathogenic	Glycogen storage disease type III	2023-10-22	criteria provided, single submitter	clinical testing