Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000672554 | SCV001443308 | likely pathogenic | Glycogen storage disease, type II | 2023-03-10 | reviewed by expert panel | curation | The NM_000152.5:c.768dup (p.Ile257TyrfsTer73) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). The variant has been reported in a patient with Pompe disease but further details regarding the second variant and residual GAA activity are unavailable (PMID: 18425781). There is a ClinVar entry for this variant (Variation ID: 556534). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). |
| Counsyl | RCV000672554 | SCV000797667 | likely pathogenic | Glycogen storage disease, type II | 2018-02-06 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000672554 | SCV004296861 | pathogenic | Glycogen storage disease, type II | 2023-02-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556534). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 18425781). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile257Tyrfs*73) 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). |