ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1798C>T (p.Arg600Cys) (rs764670084)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000794042 SCV000933425 pathogenic Glycogen storage disease, type II 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 600 of the GAA protein (p.Arg600Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs764670084, ExAC 0.006%). This variant has been observed in combination with another GAA variant in several individuals affected with Pompe disease (PMID: 29124014, 11053688, 20202878, 25213570, 27344650, 29044175). This variant has been reported to affect GAA protein function (PMID: 11053688). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000794042 SCV001363614 pathogenic Glycogen storage disease, type II 2021-07-05 criteria provided, single submitter clinical testing Variant summary: GAA c.1798C>T (p.Arg600Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248436 control chromosomes. c.1798C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Tsujino_2000, Hermans_2004). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Tsujino_200, Hermans_2004). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000794042 SCV001422995 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg600Cys variant in GAA has been reported in at least 14 individuals with glycogen storage disease II (PMID: 24384324, 19609281, 21982629, 20202878, 18458862, 14695532, 11053688) and has been identified in 0.003% (1/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs764670084). 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 using COS cells and fibroblast cells transfected with the variant provide some evidence that the p.Arg600Cys variant may impact protein function (PMID: 11053688, 14695532). However, these types of assays may not accurately represent biological function. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <10% of wild type, consistent with disease (PMID: 24384324, 19609281, 21982629, 18458862, 14695532, 14643388). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported pathogenic and likely pathogenic variants and in 8 individuals with glycogen storage disease II increases the likelihood that the p.Arg600Cys variant is pathogenic (VariationID: 371305, 4033, 189172; PMID: 24384324, 19609281, 21982629, 20202878, 18458862, 14695532, 14643388). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 370130; PMID: 22676651, 21920843, 18757064, 27649523, 24715333, 18995995, 10338092). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individuals, in vitro studies demonstrating an impact on protein function, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PM3_strong, PS3, PM5, PM2, PP3, PP4 (Richards 2015).

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