ClinVar Genomic variation as it relates to human health

The heterozygous c.692+5G>T variant in GAA has been reported in the compound heterozygous state in 2 individuals of northwestern European descent with Glycogen Storage Disease II (PMID: 24384324, 26873529). This variant has been identified in 0.001% (1/111074) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763027848). 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 has also been reported as a VUS by Invitae in ClinVar (Variation ID: 526532). In vitro RT-PCR with patient muscle cell RNA provides some evidence that the c.692+5G>T variant may impact mRNA expression levels (PMID: 24384324). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the c.692+5G>T variant is pathogenic (PMID: 24384324). The phenotype of 2 individuals with the variant in the heterozygous state is highly specific for Glycogen Storage Disease II based on reduced GAA activity compared to controls in relevant tissue (PMID: 24384324, 26873529). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PS3_Supporting, PP4 (Richards 2015).

This sequence change falls in intron 3 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs763027848, gnomAD 0.0009%). This variant has been observed in individual(s) with Pompe disease (PMID: 24384324, 26873529, 29181627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 526532). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.