ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1726G>A (p.Gly576Ser) (rs1800307)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078161 SCV000109999 benign not specified 2017-05-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000078161 SCV000302667 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000353996 SCV000407284 benign Glycogen storage disease, type II 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000431108 SCV000510579 benign not provided 2016-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000431108 SCV000521131 benign not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 9266392, 21644219, 18301443, 14643388, 17805474, 28725570)
Invitae RCV000353996 SCV000626522 other Glycogen storage disease, type II 2018-12-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000431108 SCV000695646 benign not provided 2017-05-03 criteria provided, single submitter clinical testing Variant summary: The GAA c.1726G>A (p.Gly576Ser) variant involves the alteration of a conserved nucleotide resulting in a missense substitution in the glycoside hydrolase superfamily domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC in 2266 of 121736 control chromosomes (124 homozygotes) from all ethnicities, but was predominantly observed in the East Asian subpopulation at a frequency of 0.144416 (1244/8614; 109 homozygotes). This frequency is about 34 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), strongly suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant and its haplotype complex, p.[G576S; E689K], are widely regarded as a variant causing pseudodeficiency of alfa-glucosidase. The subjects who carried the p.[G576S;E689K] in homozygous state or compound heterozygous state with a truncating variant were not found to clinically manifest Pompe disease, yet they had a reduced enzymatic activity (Kroos_EJHG_2008). In addition, this variant has also been found in cis with two known pathogenic variants (p. Asp645Glu and p.Trp746Cys) in patients with Pompe disease (Yang_MGM_2011), strongly suggesting for a benign outcome. In vitro functional studies are consistent with this variant being a functional polymorphism; this variant maintains a residual activity and it can significantly reduce the functional activity of a potentially pathogenic variant when found in cis (Pipo_Peditr Neurol_2003; Yang_MGM_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000353996 SCV001158935 benign Glycogen storage disease, type II 2020-08-25 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000078161 SCV000151252 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
GenomeConnect - Invitae Patient Insights Network RCV000353996 SCV001749549 not provided Glycogen storage disease, type II no assertion provided phenotyping only Variant interpreted as Benign and reported on 03-18-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
GeneReviews RCV000353996 SCV001761182 other Glycogen storage disease, type II 2017-05-11 no assertion criteria provided literature only Pseudodeficiency allele c.1726 G>A (p.Gly576Ser), which interferes with enzyme activity toward artificial substrates, is relatively common in Asian as well as other populations studied as part of newborn screening programs.

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