Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000169565 | SCV001371766 | pathogenic | Glycogen storage disease, type II | 2020-02-14 | reviewed by expert panel | curation | This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP's specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this 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, PM3, PP4. |
Counsyl | RCV000169565 | SCV000221062 | likely pathogenic | Glycogen storage disease, type II | 2015-01-22 | criteria provided, single submitter | literature only | |
Eurofins Ntd Llc |
RCV000727554 | SCV000854784 | pathogenic | not provided | 2018-08-20 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000169565 | SCV001228766 | pathogenic | Glycogen storage disease, type II | 2023-06-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189144). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12897283, 24269976, 25846667, 29124014). This variant is present in population databases (rs754952153, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr609*) 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). |
Broad Center for Mendelian Genomics, |
RCV000169565 | SCV001422877 | pathogenic | Glycogen storage disease, type II | 2020-01-22 | criteria provided, single submitter | curation | The p.Tyr609Ter variant in GAA has been reported in at least 4 individuals (including at least 1 Dutch individual) with Glycogen Storage Disease II (PMID: 14695532, 12897283, 25741864, 22252923), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 189144). This variant has been identified in 0.00002% (2/110126) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778892297). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant leads to a premature termination codon at position 609, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr609Ter variant is pathogenic (PMID: 25741864, 12897283). Another pathogenic variant, c.1827delC (p.Tyr609Ter), has been reported with the same position and amino acid change (PMID: 14695532, 26693141). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on multiple reports of this variant in CRIM-negative cohorts and abnormally low GAA activity detected in the fibroblasts of one individual heterozygous for this variant (PMID: 22252923, 25741864, 12897283). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015). |
Gene |
RCV000727554 | SCV002571489 | pathogenic | not provided | 2023-07-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via a mouse model homozygous knock-in for the p.(Y609X) variant that has features of Infantile-onset Pompe Disease (IOPD) (Huang et al., 2020); 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; This variant is associated with the following publications: (PMID: 31254424, 33301762, 12897283, 25846667, 29124014, 32587263) |
Baylor Genetics | RCV000169565 | SCV004197871 | pathogenic | Glycogen storage disease, type II | 2023-01-27 | criteria provided, single submitter | clinical testing |