ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1100G>A (p.Trp367Ter)

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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 RCV001248955 SCV001422741 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp367Ter variant in GAA has been reported in one Caucasian individual with glycogen storage disease (PMID: 17723315, 18425781), and been identified in 0.001% (1/112382) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs1478500490). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier disease. This nonsense variant leads to a premature termination codon at position 367, 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. The presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17723315) and in an individual with glycogen storage disease increases the likelihood that the p.Trp367Ter variant is pathogenic. The phenotype of an individual compound heterozygous for this variant is highly specific for glycogen storage disease based on their GAA activity being less than 10% of WT, consistent with disease (PMID: 17723315). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on its prediction to cause loss of function of GAA, and its presence in an affected individual with another pathogenic variant. ACMG/AMP Criteria applied: PVS1, PM2, PM3_supporting, PP4 (Richards 2015).

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