Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000665079 | SCV001371765 | pathogenic | Glycogen storage disease, type II | 2020-04-21 | reviewed by expert panel | curation | This variant, c.989G>A (p.Trp330Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Two individuals with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported in the literature. These individuals are non-identical twins and are compound heterozyous for the variant and c.1655T>C (p.Leu552Pro); this in trans data was used in the assessment of p.Leu552Pro and therefore was not included here in order to avoid a circular argument. Another individual was reported to be compound heterozygous for the variant and c.-32-13T>G (PMID 29880332). While this patient was described as having reduced GAA activity in dried blood spots, the normal range for the assay was not provided and therefore this data was not included. The variant is absent in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID 550355; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. |
| Counsyl | RCV000665079 | SCV000789140 | likely pathogenic | Glycogen storage disease, type II | 2017-01-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000665079 | SCV001387412 | pathogenic | Glycogen storage disease, type II | 2023-07-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change creates a premature translational stop signal (p.Trp330*) 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12923862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 550355). |
| Gene |
RCV002289951 | SCV002578804 | pathogenic | not provided | 2022-04-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; Reported in ClinVar as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (ClinVar Variant ID#550355; SCV001371765.1 ); This variant is associated with the following publications: (PMID: 25525159, 18425781, 22252923, 12923862, 29880332) |
| Baylor Genetics | RCV000665079 | SCV004197816 | pathogenic | Glycogen storage disease, type II | 2023-06-12 | criteria provided, single submitter | clinical testing |