ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1725C>A (p.Tyr575Ter)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV001248863 SCV001422536 pathogenic Glycogen storage disease, type II 2020-01-15 no assertion criteria provided curation The p.Tyr575Ter variant in GAA has been reported in one Finnish individual with glycogen storage disease II (PMID: 19472353, 25047669) and has been identified in 0.020% (5/25062) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112517802). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 575, 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. Additionally, this variant has been reported in combination with reported likely pathogenic variant p.Pro545Leu (VariationID: 4032, PMID: 19472353) and in an individual with glycogen storage disease II. The phenotype of an individual compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA activity less than 10% of WT, consistent with disease (PMID: 19472353). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the prediction that it will cause loss of function of the GAA gene and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).

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