ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.875A>G (p.Tyr292Cys) (rs1057516600)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410689 SCV000485930 likely pathogenic Glycogen storage disease, type II 2016-03-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000730212 SCV000857931 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000410689 SCV000919380 pathogenic Glycogen storage disease, type II 2018-04-16 criteria provided, single submitter clinical testing Variant summary: GAA c.875A>G (p.Tyr292Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 8.3e-06 in 241494 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (8.3e-06 vs 0.0042), allowing no conclusion about variant significance. The variant, c.875A>G, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Gort_2007, Gutierrez-Rivas_2015, Hermans_2004, Park_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000410689 SCV001410595 pathogenic Glycogen storage disease, type II 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 292 of the GAA protein (p.Tyr292Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glycogen storage disease type II (PMID: 10528311, 25213570, 23884227, 21940687). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370577). This variant has been reported to affect GAA protein function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000410689 SCV001422622 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Tyr292Cys variant in GAA has been reported in 8 individuals (including 3 Spanish, 2 Dutch, 2 Korean, and 1 Dominican/Caucasian individuals) with Glycogen Storage Disease II (PMID: 10528311, 25998610, 17616415, 14695532, 23884227, 11927738), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 370577). This variant has been identified in 0.006% (2/34222) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516600). 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 this variant provide some evidence that the p.Tyr292Cys variant may impact GAA activity (PMID: 19862843, 14695532, 11927738). 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 pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr292Cys variant is pathogenic (PMID: 10528311, 17616415). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected by assays of relevant tissues, consistent with disease (PMID: 17616415, 11927738, 10528311). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on evidence from in vitro functional studies and multiple occurrences with variants associated with disease in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015).

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