Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001201750 | SCV002540649 | pathogenic | Glycogen storage disease, type II | 2022-01-04 | reviewed by expert panel | curation | The NM_000152.5(GAA):c.1396del (p.Val466PhefsTer11) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 3 probands with residual GAA activity below the normal range or <10% normal (PMIDs 18285536, 23601496, 25786784) one of whom is also reported to be CRIM-negative and to have clinical improvements when on enzyme replacement therapy (PMID 23601496), as well as in an adult proband and her affected sibling with muscle weakness (PP4_Moderate). Three of these probands are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.-32-13T>G (PMID 25786784), c.2238G>C (p.Trp746Cys) (PMID 25526786), or c.1705dupT (PMID 23601496) Another proband is compound heterozygous for the variant and c.784G>A (p.Gln262Lys) (PMID 18285536); the allelic data from this patient was used in the assessment of p.Gln262Lys and is not included here to avoid circular logic (PM3). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PM3, PP4_Moderate, PM2_Supporting. |
| Invitae | RCV001201750 | SCV001372837 | pathogenic | Glycogen storage disease, type II | 2019-09-15 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant has been observed in an individual affected with glycogen storage disease 2 (PMID: 18285536). This sequence change creates a premature translational stop signal (p.Val466Phefs*11) in the GAA gene. It is expected to result in an absent or disrupted protein product. |