Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001249046 | SCV001422991 | likely pathogenic | Glycogen storage disease, type II | 2020-01-14 | criteria provided, single submitter | curation | The c.1888+1G>A variant in GAA has been reported in at least three individuals with glycogen storage disease (PMID: 18425781, 25786784, 21803581) and has been identified in 0.001% (1/101592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776325453). 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). |
| Invitae | RCV001249046 | SCV001577049 | likely pathogenic | Glycogen storage disease, type II | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 13 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 18425781). ClinVar contains an entry for this variant (Variation ID: 972800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV001249046 | SCV004195516 | pathogenic | Glycogen storage disease, type II | 2023-08-07 | criteria provided, single submitter | clinical testing |