ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1952del (p.Gly651fs) (rs1567835775)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000780269 SCV001443292 likely pathogenic Glycogen storage disease, type II 2020-10-29 reviewed by expert panel curation This variant, c.1952del (p.Gly651AlafsTer45) is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. The variant is absent in gnomAD v2.1.1, meeting PM2. Two adult siblings with limb girdle muscular weakness have been reported who are compound heterozygous for the variant (labeled as c.1951del in the publication, but since c.1950, 1951, and 1952 are all G's. this is the same as c.1952del) and c.-32-13T>G (PMID 31125121). While GAA activity was deficient in dried blood spots, several patients in this screening study appear to have false positive enzyme deficiency. Therefore, PP4 and PM3 were not met. There is a ClinVar entry for this variant (Variation ID: 632822, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780269 SCV000917393 likely pathogenic Glycogen storage disease, type II 2018-03-20 criteria provided, single submitter clinical testing Variant summary: GAA c.1952delG (p.Gly651AlafsX45) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2544delC/p.Lys849fsX38, c.2560C>T/p.Arg854X). The variant was absent in 89202 control chromosomes (ExAC). To our knowledge, no occurrence of c.1952delG in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780269 SCV001585207 pathogenic Glycogen storage disease, type II 2020-10-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly651Serfs*45) in the GAA gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This variant has been observed in individual(s) with Pompe disease (PMID: 31392188). ClinVar contains an entry for this variant (Variation ID: 632822). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.