Submissions for variant NM_000642.3(AGL):c.1571G>A (p.Arg524His)

gnomAD frequency: 0.00001  dbSNP: rs758182700

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001047067	SCV001211001	pathogenic	Glycogen storage disease type III	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 524 of the AGL protein (p.Arg524His). This variant is present in population databases (rs758182700, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycogen storage disease III (PMID: 16705713, 22089644, 26984562). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 844261). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGL protein function. Experimental studies have shown that this missense change affects AGL function (PMID: 27088557). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001047067	SCV002015132	pathogenic	Glycogen storage disease type III	2021-10-30	criteria provided, single submitter	clinical testing	Variant summary: AGL c.1571G>A (p.Arg524His) 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 allele was found at a frequency of 4e-06 in 251208 control chromosomes. c.1571G>A has been reported in the literature in individuals affected with Glycogen Storage Disease Type III (example, Lucchiari_2006, Mili_2012, Lu_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Zhai_2016). The most pronounced variant effect results in <10% of normal debranching enzyme specific activity. One clinical diagnostic laboratory has 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.
Genome-Nilou Lab	RCV001047067	SCV002055480	pathogenic	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001047067	SCV004171272	pathogenic	Glycogen storage disease type III		criteria provided, single submitter	clinical testing	The missense c.1571G>A(p.Arg524His) variant in AGL gene has been reported in homozygous state in individuals affected with Glycogen storage disease (Çakar NE, et. al.,2020). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submission). The amino acid change p.Arg524His in AGL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 524 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001047067	SCV004211290	pathogenic	Glycogen storage disease type III	2023-07-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480922	SCV004226531	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_strong, PS4_moderate
Natera, Inc.	RCV001047067	SCV002091501	pathogenic	Glycogen storage disease type III	2021-06-29	no assertion criteria provided	clinical testing