ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1962_1964del (p.Glu656del)

gnomAD frequency: 0.00001  dbSNP: rs1030961946
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001200864 SCV001371734 pathogenic Glycogen storage disease, type II 2020-05-05 reviewed by expert panel curation This variant, c.1962_1964delAGA, is predicted to result in an inframe deletion of one amino acid in GAA, p.Glu656del, meeting PM4_Supporting. This variant is not present in gnomAD v2.1.1, meeting PM2. From unpublished clinical laboratory data, three patients with this variant meet the ClinGen LSD VCEP's specifications for PP4. One of these individuals is homozygous for the variant and the parents are confirmed to be heterozygous; one individual is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter); and one individual is compound heterozygous for the variant and c.883C>A (p.His295Asn). Based on this data, PM3 is met. At least one Indian patient with this variant has been described but full details, such as reference range for GAA activity, were not provided and therefore the data was not included (PMIDs 22711147, 22791670). When expressed in COS-7 cells, the variant has 2% wild type GAA activity and exhibits abnormal GAA processing on Western blot (PMID 18425781), meeting PS3. PROVEAN and Mutation Taster predict that the variant has a deleterious impact on protein function, meeting PP3. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3, PM4_Supporting, PP3, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001200864 SCV001774624 pathogenic Glycogen storage disease, type II 2021-07-30 criteria provided, single submitter clinical testing Variant summary: GAA c.1962_1964delAGA (p.Glu656del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 242422 control chromosomes (gnomAD). c.1962_1964delAGA has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Kroos_2008, Gupta_2020). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant has a severe effect on enzyme activity (Kroos_2008). An expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) (evaluation after 2014) cites the variant as pathogenic in ClinVar, reporting unpublished clinical laboratory data of three patients with this variant (1 homozygous, 2 compound heterozygous). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001200864 SCV002309173 likely pathogenic Glycogen storage disease, type II 2023-05-19 criteria provided, single submitter clinical testing This variant, c.1962_1964del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Glu656del), but otherwise preserves the integrity of the reading frame. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects GAA function (PMID: 18425781). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 932896). This variant is also known as p.Glu655del. This variant has been observed in individuals with clinical features of Pompe disease (PMID: 18425781, 22711147, 22791670, 31606152, 32504392). This variant is not present in population databases (gnomAD no frequency).
Fulgent Genetics, Fulgent Genetics RCV001200864 SCV002794796 pathogenic Glycogen storage disease, type II 2022-03-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV001200864 SCV004197840 likely pathogenic Glycogen storage disease, type II 2023-04-26 criteria provided, single submitter clinical testing

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.