ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2331+2T>A (rs1057517148)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411608 SCV000486824 pathogenic Glycogen storage disease, type II 2016-08-18 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000411608 SCV001423063 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The c.2331+2T>A variant in GAA has been reported in at least 4 individuals (including 1 Belgian individual) with Glycogen Storage Disease II (PMID: 22252923, 18425781, 20817528), and has also been reported pathogenic by Counsyl in ClinVar (Variation ID: 371281). This variant has been identified in 0.001% (1/111712) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057517148). 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 abnormal 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 a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the c.2331+2T>A variant is pathogenic (PMID: 20817528). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their fibroblasts (PMID: 20817528). 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 an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PM2, PP4 (Richards 2015).

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