ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.655G>A (p.Gly219Arg) (rs370950728)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169462 SCV000220892 likely pathogenic Glycogen storage disease, type II 2014-11-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000481943 SCV000330942 pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000481943 SCV000565024 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The G219R pathogenic variant in the GAA gene was first reported in an individual with infantile GSDII, who harbored an additional GAA variant (Fernandez-Hojas et al., 2002). G219R has subsequently been reported, in both the homozygous state and along with an additional GAA variant, in multiple individuals with GSDII (Hermans et al., 2004; Prater et al., 2013; Sacconi et al., 2014). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G219R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (P217L; R224W/Q/P) have been reported in the Human Gene Mutation Database in association with GSDII (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000169462 SCV000695664 pathogenic Glycogen storage disease, type II 2017-05-07 criteria provided, single submitter clinical testing Variant summary: The GAA c.655G>A (p.Gly219Arg) variant located in the Galactose mutarotase, N-terminal barrel domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120140 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in both compound heterozygous and homozygous Pompe disease patients, which were found to have very little GAA activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Invitae RCV000169462 SCV000626621 pathogenic Glycogen storage disease, type II 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 219 of the GAA protein (p.Gly219Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs370950728, ExAC 0.01%). This variant has been reported in individuals affected with Pompe disease (PMID: 11738358, 14695532, 18429042, 21550241, 23266370, 23787031, 24844452, 25037089), and has been observed in two individuals with low GAA activity (PMID: 23601496, 29124014). ClinVar contains an entry for this variant (Variation ID: 189065). Experimental studies have shown that this missense change reduces GAA enzyme activity in vitro (PMID: 14695532). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.