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

Total submissions: 9

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	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000353996	SCV001158935	benign	Glycogen storage disease, type II	2018-12-12	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.