ClinVar Genomic variation as it relates to human health

This sequence change is a substitution in intron 18, c.2647-7G>A. This sequence change has been described in the gnomAD database with a low frequency of 0.003% in the south Asian and non-Finnish European subpopulations (rs192679574). This sequence change has been previously described in a family with late-onset Pompe disease and segregates with the disease phenotype (PMID: 24107549). Functional studies show c.2647-7G>A causes a splicing defect (PMID: 24107549). Based on these evidence, the c.2647-7G>A variant is classified as likely pathogenic.

The c.2647-7G>A variant in GAA has been reported in at least 9 Italian individuals with glycogen storage disease, segregated with disease in 9 affected relatives from 1 family (PMID: 24107549), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.003% (4/128816) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs192679574). 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 in ClinVar (Variation: 551106) as Likely Pathogenic by Counsyl. In vitro functional studies provide some evidence that the c.2647-7G>A variant may slightly impact protein function by showing presence of alternatively spliced transcripts that result in NMD (PMID: 24107549). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. The nucleotide at position 2647-7 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational tools do suggest an impact to splicing resulting in a cryptic acceptor splice site that causes a frameshift. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle being <10% of wild type, consistent with disease (PMID: 24107549). Additionally, the presence of this variant in combination with a reported pathogenic variant p.Arg40Ter (VariationID: 426593; PMID: 24107549) in seven siblings with glycogen storage disease slightly increases the likelihood that the c.2647-7G>A variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_supporting, PM2, PP4, PP3, PS3_supporting (Richards 2015).

Variant summary: GAA c.2647-7G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 prime acceptor site. One predict the variant weakens a canonical 3 prime acceptor site. Four predict the variant creates a cryptic 3 prime acceptor site. Sampaolo_ 2013 have demostrated this variant leads to a reduction in wild type mRNA levels consistent with the abolishment of the canonical 3' acceptor site. The variant allele was found at a frequency of 1.6e-05 in 249470 control chromosomes (gnomAD). c.2647-7G>A has been reported in the literature in multiple compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and variant segregated with the disease (Sampaolo_GAA_OJRD_2013). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change falls in intron 18 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. This variant is present in population databases (rs192679574, gnomAD 0.003%). This variant has been observed in individual(s) with late-onset glycogen storage disease (PMID: 24107549). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551106). 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.