ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1826dup (p.Tyr609Ter) (rs786204727)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000169565 SCV001371766 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP's specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4.
Counsyl RCV000169565 SCV000221062 likely pathogenic Glycogen storage disease, type II 2015-01-22 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727554 SCV000854784 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing
Invitae RCV000169565 SCV001228766 pathogenic Glycogen storage disease, type II 2019-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr609*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs754952153, ExAC 0.003%). This nonsense change has been observed in individual(s) with Pompe disease (PMID: 12897283, 25846667, 29124014, 24269976). ClinVar contains an entry for this variant (Variation ID: 189144). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169565 SCV001422877 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Tyr609Ter variant in GAA has been reported in at least 4 individuals (including at least 1 Dutch individual) with Glycogen Storage Disease II (PMID: 14695532, 12897283, 25741864, 22252923), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 189144). This variant has been identified in 0.00002% (2/110126) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778892297). 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 leads to a premature termination codon at position 609, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr609Ter variant is pathogenic (PMID: 25741864, 12897283). Another pathogenic variant, c.1827delC (p.Tyr609Ter), has been reported with the same position and amino acid change (PMID: 14695532, 26693141). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on multiple reports of this variant in CRIM-negative cohorts and abnormally low GAA activity detected in the fibroblasts of one individual heterozygous for this variant (PMID: 22252923, 25741864, 12897283). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

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