Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000411398 | SCV002032115 | pathogenic | Glycogen storage disease, type II | 2021-08-27 | reviewed by expert panel | curation | The NM_000152.5: c.2281delinsAT (p.Ala761IlefsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, 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 patients with Pompe disease including one individual with documentation of laboratory values showing GAA deficiency, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 17056254), and another stated to have deficient GAA activity (laboratory values not available) and on enzyme replacement therapy, meeting PP4 (PMID 29181627)(PP4_Moderate was applied). Both of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (2 x 0.5 points = 1 point, PM3). Another patient was identified by newborn screening and was compound heterozygous for the variant, c.2238G>C (p.Trp746Cys), and a pseudodeficiency variant, c.2065G>A (PMID 33202836). This data may be used in the assessment of p.Trp746Cys and was not included here to avoid circular logic. The c.2281delinsAT variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370993, 2 star review status) with one submitter 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 (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. |
| Counsyl | RCV000411398 | SCV000486440 | likely pathogenic | Glycogen storage disease, type II | 2016-06-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000411398 | SCV000963069 | pathogenic | Glycogen storage disease, type II | 2023-08-16 | criteria provided, single submitter | clinical testing | Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Ala761Ilefs*35) 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 premature translational stop signal has been observed in individual(s) with late-onset Pompe disease (PMID: 17056254). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV002461133 | SCV002756598 | pathogenic | not provided | 2022-05-18 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32721234, 29181627, 33202836, 17056254) |
| Baylor Genetics | RCV000411398 | SCV004195438 | pathogenic | Glycogen storage disease, type II | 2023-10-20 | criteria provided, single submitter | clinical testing |