Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000169394 | SCV001371741 | pathogenic | Glycogen storage disease, type II | 2020-02-14 | reviewed by expert panel | curation | This variant, c.2608C>T (p.Arg870Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant has been reported in patients meeting the ClinGen LSD VCEP's PP4 criterion who also carry a known pathogenic variant in GAA, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). There is a ClinVar entry for this variant (Variation ID: 189009, 2 star review status) with five submitters 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. |
Counsyl | RCV000169394 | SCV000220788 | likely pathogenic | Glycogen storage disease, type II | 2014-10-14 | criteria provided, single submitter | literature only | |
Eurofins Ntd Llc |
RCV000723528 | SCV000700543 | pathogenic | not provided | 2017-06-01 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000723528 | SCV000890293 | pathogenic | not provided | 2019-01-11 | criteria provided, single submitter | clinical testing | The R870X variant has been reported in a patient with infantile onset glycogen storage disease II (GSDII) who was homozygous for the R870X variant (Swift et al., 2017). The R870X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R870X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic. |
Fulgent Genetics, |
RCV000169394 | SCV000893479 | pathogenic | Glycogen storage disease, type II | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000169394 | SCV001223553 | pathogenic | Glycogen storage disease, type II | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg870*) 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 present in population databases (rs780321415, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 17056254, 27344650, 29181627). ClinVar contains an entry for this variant (Variation ID: 189009). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169394 | SCV001339199 | pathogenic | Glycogen storage disease, type II | 2020-03-05 | criteria provided, single submitter | clinical testing | Variant summary: GAA c.2608C>T (p.Arg870X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.7e-05 in 225354 control chromosomes (gnomAD). c.2608C>T has been reported in the literature in multiple compound heterozygous- and homozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. McCready_2007, Palmer_2007, Swift_2016, Banugaria_2013, Loscher_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Broad Center for Mendelian Genomics, |
RCV000169394 | SCV001422606 | pathogenic | Glycogen storage disease, type II | 2020-01-22 | criteria provided, single submitter | curation | The p.Arg870Ter variant in GAA has been reported in 9 individuals (including 2 Brazilian, 2 from the UK, 1 Spanish, 1 German, and 1 Hispanic individuals) with Glycogen Storage Disease II (PMID: 23843830, 22676651, 17056254, 17723315, 26497565, 23825616, 19588081, 25681614), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189009). This variant has been identified in 0.005% (5/102290) of European (non-Finnish) chromosomes and 0.003% (1/31448) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs780321415). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 870, 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 2 pathogenic variants and in homozygosity in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg870Ter variant is pathogenic (PMID: 22676651, 26497565). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity detected (PMID: 26497565, 22676651). 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). |
Revvity Omics, |
RCV000723528 | SCV002023824 | pathogenic | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | |
Neuberg Centre For Genomic Medicine, |
RCV000169394 | SCV004100427 | pathogenic | Glycogen storage disease, type II | criteria provided, single submitter | clinical testing | The stop gained c.2608C>T (p.Arg870Ter) variant in GAA gene has been reported previously in both homozygous and compound heterozygous state in multiple individuals affected with Glycogen storage disease II (Broomfield et al. 2016; Swift et al. 2017; Löscher et al. 2018). The c.2608C>T variant variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.2608C>T in GAA is predicted as conserved by PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. | |
Baylor Genetics | RCV000169394 | SCV004195439 | pathogenic | Glycogen storage disease, type II | 2024-03-28 | criteria provided, single submitter | clinical testing | |
Molecular Therapies Laboratory, |
RCV000169394 | SCV001244230 | pathogenic | Glycogen storage disease, type II | 2019-01-07 | no assertion criteria provided | research | Adult form; onset in third decade; normal size and amount of mRNA for GAA, GAA protein detected by antibody, but only 9 to 26% of normal acid-alpha-1,4 glucosidase activity |
Genome Diagnostics Laboratory, |
RCV000723528 | SCV001931979 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000723528 | SCV001959263 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000723528 | SCV001973296 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Natera, |
RCV000169394 | SCV002094475 | pathogenic | Glycogen storage disease, type II | 2021-03-18 | no assertion criteria provided | clinical testing |