Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001200872 | SCV001371763 | pathogenic | Glycogen storage disease, type II | 2020-04-20 | reviewed by expert panel | curation | This variant, c.377G>A (p.Trp126Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Five individuals with Pompe disease and residual GAA activity meeting PP4 specifications have been reported with this variant (PMIDs 17056254, 25681614). One of these individuals is compound heterozygous for the variant and c.236_246del (p.Pro79ArgfsX13); as the mother is heterozygous for the variant, it is likely that the variants are in trans (PMID 17056254). Another individual is the proband in a family of three siblings with late onset Pompe disease who are all compound heterozygous for the variant and c.-32-13T>G. In addition, two Brazilian siblings are compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) but this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Finally, an individual with infantile onset Pompe disease appeared to be homozygous for the variant (PMID 17056254). While the mother was heterozygous, the father was neither confirmed to be a carrier, nor appeared to have a deletion. Non-paternity was not ruled out. This data will not be included because the nature of the second variant is unclear. This in trans data meets PM3. An additional case has been reported but was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 19588081). The variant is absent in gnomAD v2.1.1, meeting PM2. There is no ClinVar entry for this variant. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. |
| Invitae | RCV001200872 | SCV002238321 | pathogenic | Glycogen storage disease, type II | 2023-09-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp126*) 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: 17056254). ClinVar contains an entry for this variant (Variation ID: 932904). For these reasons, this variant has been classified as Pathogenic. |