ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1735G>A (p.Glu579Lys) (rs991082382)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586125 SCV000695643 pathogenic Glycogen storage disease, type II 2016-09-22 criteria provided, single submitter clinical testing Variant summary: The GAA c.1735G>A (p.Glu579Lys) variant located in the glycoside hydrolase superfamily domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/5 in silico tools predicting a "damaging" outcome, which is supported by multiple functional studies. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and multiple publications cite the variant in compound heterozygote affected individuals. Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000586125 SCV001582303 pathogenic Glycogen storage disease, type II 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 579 of the GAA protein (p.Glu579Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Pompe DISEASE (PMID: 14695532, 29124014, 24269976, 31342611, 21676566). ClinVar contains an entry for this variant (Variation ID: 495664). This variant has been reported to affect GAA protein function (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000586125 SCV001132195 likely pathogenic Glycogen storage disease, type II 2018-12-27 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000586125 SCV001423068 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu579Lys variant in GAA has been reported in 4 individuals (including 1 Australian, 1 Japanese, 1 Chinese, and 1 Caucasian individuals) with Glycogen Storage Disease II (PMID: 21676566, 14695532, 24269976, 23601496), and has also been reported pathogenic by Integrated Genetics in ClinVar (Variation ID: 495664). This variant has been identified in 0.002% (2/129092) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs991082382). 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 provide some evidence that the p.Glu579Lys variant may impact GAA processing and activity (PMID: 14695532). 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 presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Glu579Lys variant is pathogenic (PMID: 23601496). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in their skin fibroblasts or muscle (PMID: 23601496, 21676566). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PS3, PM2, PP3, PP4 (Richards 2015).

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