Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000169456 | SCV002032144 | pathogenic | Glycogen storage disease, type II | 2021-08-19 | reviewed by expert panel | curation | NM_000152.5:c.365del (p.Met122ArgfsTer20) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with late onset Pompe disease has been reported with documentation of laboratory values showing GAA deficiency (~7% lower limit of normal) in cultured fibroblasts (2 points) and who is on enzyme replacement therapy (1 point)(PMID: 20638881). (Total 3 points, PP4_Moderate). This patient is compound heterozygous, with unknown phase, for the variant and a pathogenic variant in GAA, c.-32-13T>G (0.5 points, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 189059, two star review status) with two submitters classifying 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 specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. |
| Counsyl | RCV000169456 | SCV000220881 | likely pathogenic | Glycogen storage disease, type II | 2014-11-13 | criteria provided, single submitter | literature only | |
| Invitae | RCV000169456 | SCV001380433 | pathogenic | Glycogen storage disease, type II | 2021-05-25 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met122Argfs*20) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in combination with another GAA variant in an individual affected with severe, later onset Pompe disease (PMID: 20638881). ClinVar contains an entry for this variant (Variation ID: 189059). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169456 | SCV001437364 | pathogenic | Glycogen storage disease, type II | 2020-09-25 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.365delT (p.Met122ArgfsX20) 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 our laboratory. The variant was absent in 247798 control chromosomes (gnomAD v2). c.365delT has been reported in the literature in a compound heterozygous individual who was affected with the late onset form of Glycogen Storage Disease, Type 2 (Pompe Disease), where the other variant found in trans was the common disease variant, c.-32-13T>G, that is associated with the late-onset form of the disorder (Bernstein_2010). This publication also reported that the enzyme activity measured in patient derived cultured fibroblasts was about 5-7% of the normal (Bernstein_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000169456 | SCV004197844 | pathogenic | Glycogen storage disease, type II | 2023-04-18 | criteria provided, single submitter | clinical testing |