Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003061440 | SCV004227903 | uncertain significance | Glycogen storage disease, type II | 2023-12-05 | reviewed by expert panel | curation | The NM_000152.5:c.546+5G>A variant is in intron 2 of GAA. This variant has been detected in one patient with Pompe disease reported to have deficient GAA activity, but results and clinical information were not provided. This variant has also been reported in one individual with a positive newborn screen for Pompe disease and confirmed deficient GAA enzyme in DBS; while this technically meets criteria for PP4_moderate, we cannot apply this evidence code as there has not been a confirmed phenotype in this individual. This individual was compound heterozygous for this variant and the common c.-32-13T>G variant confirmed in trans (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006714 (5/74860 alleles) in the African/African-American subpopulation, which is lower than the ClinGen Lysosomal Disorders VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.57 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). There is another variant at the same location with a different amino acid change (NM_000152.5:c.546+5G>T) classified as a variant of uncertain significance by the ClinGen Lysosomal Disorders VCEP. There is a ClinVar entry for this variant (Variation ID: 2151633, 2 star review status) with two submitters classifying the variant as a uncertain significance. In summary, this variant has been classified as a VUS for Pompe disease by the ClinGen Lysosomal Disorders VCEP. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2023). |
| Labcorp Genetics |
RCV003061440 | SCV003459081 | uncertain significance | Glycogen storage disease, type II | 2024-07-19 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 2 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756024023, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 2151633). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.546+5G nucleotide in the GAA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 21232767, 31301153; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV003314053 | SCV004013378 | uncertain significance | not provided | 2023-04-13 | criteria provided, single submitter | clinical testing | PM2, PM3_Supporting, PP3 |