ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.197G>A (p.Arg66Gln)

gnomAD frequency: 0.00006  dbSNP: rs200202628
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000342526 SCV000407255 uncertain significance Glycogen storage disease, type II 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000418379 SCV000517067 likely benign not specified 2015-05-22 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 RCV000342526 SCV000626538 uncertain significance Glycogen storage disease, type II 2022-07-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the GAA protein (p.Arg66Gln). This variant is present in population databases (rs200202628, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 325775). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852725 SCV000995440 likely benign Cardiomyopathy 2019-01-24 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000342526 SCV001422668 uncertain significance Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The p.Arg66Gln variant in GAA has not been previously reported in the literature in individuals with Glycogen Storage Disease II but has been reported as a VUS by Invitae and Illumina and a likely benign variant by GeneDx in ClinVar (Variation ID: 325775). This variant has been identified in 0.020% (4/19680) of East Asian chromosomes, 0.014% (5/35104) of Latino chromosomes, and 0.002% (2/125336) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200202628). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Arginine (Arg) at position 66 is not highly conserved in mammals and evolutionary distant species, and 33 species (including Gibbon, Baboon, Rhesus, Prairie Vole, and Chinchilla) carry an Glutamine (Gln), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.Arg66Gln variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
Genome-Nilou Lab RCV000342526 SCV001810174 uncertain significance Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV003129832 SCV003816220 uncertain significance not provided 2022-03-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000342526 SCV001463468 uncertain significance Glycogen storage disease, type II 2020-01-24 no assertion criteria provided clinical testing

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