ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.692+1G>C

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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 RCV001249008 SCV001422854 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.692+1G>C variant has been reported in at least two individuals with glycogen storage disease (PMID: 24395639, 19046416, 28182897, 16917947), and has been identified in 0.001% (1/111256) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773281453). 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 occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity being <10% of wild type in fibroblasts, consistent with disease (PMID: 28182897, 16917947, 24395639). This variant has been seen in combination with reported pathogenic variant c.-32-13T>G and p.Gly549Arg (VariationID: 4027, PMID: 16917947, 16917947, 28182897, 19046416, 24395639) in individuals with glycogen storage disease. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease in an autosomal recessive manner based on the prediction that the variant causes loss of function, the detection of the variant in combination with other pathogenic variants in affected individuals, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).

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