ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1561G>A (p.Glu521Lys) (rs121907937)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169465 SCV000220900 likely pathogenic Glycogen storage disease, type II 2014-11-20 criteria provided, single submitter literature only
OMIM RCV000004237 SCV000024403 pathogenic Glycogen storage disease type II, infantile 1991-09-16 no assertion criteria provided literature only
Broad Institute Rare Disease Group,Broad Institute RCV000169465 SCV001423119 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu521Lys variant in GAA has been reported in 11 individuals (including at least 3 Caucasian and 2 Indian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 21605996, 19862843, 22704482, 1898413, 17723315, 17027861, 22676651, 25673129, 20033296, 20308911), and has been identified in 0.003% (1/30616) of South Asian chromosomes by gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907937). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported likely pathogenic by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4022). Another variant at this position, p.Glu521Val, has been reported as a VUS in association with disease in the literature (PMID: 25526786). In vitro functional studies, including transfection of COS cells and a Western Blot, provide some evidence that the p.Glu521Lys variant may impact protein processing and function (PMID: 1898413, 19862843). 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 reported pathogenic variants in compound heterozygous individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu521Lys variant is pathogenic (PMID: 25673129, 17723315, 20033296). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on GAA enzyme activity assays (PMID: 21605996, 25673129, 22676651, 20033296, 17723315, 1898413). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015).

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