ClinVar Miner

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

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Total submissions: 8
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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 likely benign Glycogen storage disease, type II 2016-06-14 criteria provided, single submitter clinical testing
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 RCV000078161 SCV000521131 benign not specified 2016-03-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000353996 SCV000626522 other Glycogen storage disease, type II 2018-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
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.

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