Table 3.
Summary of the updates made from Version 1 to Version 2 of the ACMG-AMP criteria code specifications for the classification of variants in GAA.
| Version 1 | Version 2 | Main impact | Justification | |
|---|---|---|---|---|
| Pathogenic criteria | ||||
| PS3 | Criterion applied at strong for <5% activity and moderate for 5-30% activity in appropriate functional assays. | Criterion can no longer be applied at strong; applied at moderate for <5% GAA activity AND evidence of abnormal processing; and supporting for <5% GAA activity in appropriate functional assays. | Downgraded | SVI guidance 30 |
| PM1 | Not applicable. | Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA. | Added | Re-evaluation by VCEP members |
| PM2 | If the threshold is met, apply at moderate strength. | If threshold is met, apply at supporting strength, based on SVI recommendations. | Downgraded | SVI guidance (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf) |
| PM3 | Cases must meet PP4 to be counted for PM3 | Cases are no longer required to meet the strict PP4 criterion in order to be counted for PM3. However, some evidence for the diagnosis of Pompe disease must be present. | Allows use of additional data | Re-evaluation by VCEP members |
| PP4 | Specific values for residual activity must be available and meet the criteria. | A point-based system was developed to allow the use of additional data. | Allows use of additional data | Re-evaluation by VCEP members |
| Benign criteria | ||||
| BS2 | Not applicable. | Homozygous individual of any age with normal GAA activity. | Added | Re-evaluation by VCEP members |
| BS3 | Criterion applied at strong for >60% activity, moderate for 40-60% activity in appropriate functional assays, or 30-60% activity if evidence of normal synthesis and processing is also available. | Criterion can no longer be applied at strong; applied at supporting for >50% activity in appropriate functional assays, and >30% activity if evidence of normal synthesis and processing is also available. | Downgraded | SVI guidance 30 |