ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2015G>A (p.Arg672Gln) (rs778418246)

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
Counsyl RCV000410731 SCV000486623 likely pathogenic Glycogen storage disease, type II 2016-07-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000410731 SCV000917384 pathogenic Glycogen storage disease, type II 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The GAA c.2015G>A (p.Arg672Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/237400 control chromosomes at a frequency of 0.0000211, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state, and has been reported in homozygous patients to lead to complete loss of acid maltase activity (Tsujino_GAA_ND_2000). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000410731 SCV000939597 pathogenic Glycogen storage disease, type II 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 672 of the GAA protein (p.Arg672Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs778418246, ExAC 0.01%). This variant has been observed in individuals affected with Pompe disease, including individuals with low alpha-glucosidase enzyme activity (less than 40% of normal), findings that are highly specific for this disease (PMID: 23884227, 11053688, 28592009, 25712382). This variant has been reported in an individual affected with inherited muscular disorder (PMID: 27363342). ClinVar contains an entry for this variant (Variation ID: 371126). Experimental studies have shown that this missense change results in severely reduced alpha-glucosidase enzyme activity (PMID: 9535769, 19862843, 28592009). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg672 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9535769, 21484825, 21757382, 15986226, 16917947, 19862843), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.