Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001225163 | SCV005089699 | pathogenic | Glycogen storage disease, type II | 2024-04-15 | reviewed by expert panel | curation | The NM_000152.5:c.1579del (p.Arg527GlyfsTer51) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 12 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant was identified by newborn screening in Taiwan, with a predicted severe/classical phenotype, with confirmatory GAA deficiency "defined as lymphocyte GAA activity <3% of the normal mean", and absence of the pseudodeficiency variant c.1726G>A. The patient was reported to be on enzyme replacement therapy based on an "unrecorded indication" (PMID: 34995642) (PP4_Moderate). This patient is compound heterozygous for the variant and c.1222A>G (p.Met408Val) (ClinVar Variation ID: 371235); the variants are confirmed to be in trans (PMID: 34995642). The allelic data from this patient has been used in the classification of p.Met408Val and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2024) |
| Labcorp Genetics |
RCV001225163 | SCV001397402 | pathogenic | Glycogen storage disease, type II | 2022-09-15 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 952947). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg527Glyfs*51) 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). |
| Fulgent Genetics, |
RCV001225163 | SCV005653210 | likely pathogenic | Glycogen storage disease, type II | 2024-01-28 | criteria provided, single submitter | clinical testing |