Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000669955 | SCV002583367 | pathogenic | Glycogen storage disease, type II | 2022-09-06 | reviewed by expert panel | curation | The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID: 31710733), and another is homozygous for the variant (PMID: 22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as pathogenic and one as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. |
| Counsyl | RCV000669955 | SCV000794758 | likely pathogenic | Glycogen storage disease, type II | 2017-10-16 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000669955 | SCV001589427 | pathogenic | Glycogen storage disease, type II | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys903Argfs*2) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923). ClinVar contains an entry for this variant (Variation ID: 554339). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000669955 | SCV002051424 | pathogenic | Glycogen storage disease, type II | 2021-12-30 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.2706delG (p.Lys903ArgfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by HGMD. The variant was absent in 250632 control chromosomes (gnomAD). c.2706delG has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Bali_2012, Khan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000669955 | SCV004197860 | pathogenic | Glycogen storage disease, type II | 2023-03-09 | criteria provided, single submitter | clinical testing |