ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.671G>A (p.Arg224Gln) (rs200210219)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000822702 SCV000963515 likely pathogenic Glycogen storage disease, type II 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 224 of the GAA protein (p.Arg224Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs200210219, ExAC 0.01%). This variant has been observed in an individual affected with Pompe disease (PMID: 23000108). ClinVar contains an entry for this variant (Variation ID: 664582). Experimental studies have shown that this missense change impairs enzyme activity (PMID: 23000108, 22644586). This variant disrupts the p.Arg224 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 8429042, 14643388, 12923862, 25026126), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000822702 SCV001422855 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg224Gln variant in GAA has been reported in 4 individuals with glycogen storage disease II (PMID: 23147228, 23000108, 21488293, 22644586), and has been identified in 0.008% (2/24814) of African chromosomes, 0.005% (1/19926) of East Asian chromosomes, and 0.003% (1/35358) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200210219). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with the variant provide some evidence that the p.Arg224Gln variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <1% of normal in fibroblasts and lymphocytes, consistent with disease (PMID: 23000108). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg224Pro, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22644586, 20080426). Additionally, the presence of this variant in combination with reported pathogenic variant c.525delT (VariationID: 4033) and in two individuals with glycogen storage disease II increases the likelihood that the p.Arg224Gln variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on the predicted impact on the protein based on in vitro functional studies and computational evidence, the low frequency of the variant in the general population, and the detection of the variant in affected individuals also harboring another pathogenic variant. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PM5_Supporting, PP4 (Richards 2015).

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