ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2105G>T (p.Arg702Leu) (rs398123172)

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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174831 SCV000226206 likely pathogenic not provided 2013-06-19 criteria provided, single submitter clinical testing
Invitae RCV000792061 SCV000931333 pathogenic Glycogen storage disease, type II 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 702 of the GAA protein (p.Arg702Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GAA variant in individuals affected with infantile onset Pompe disease (PMID: 29122469, 27344650, 22252923). ClinVar contains an entry for this variant (Variation ID: 92472). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg702 amino acid residue in GAA. Other variants that disrupt this residue have been observed in affected individuals (PMID: 18211760, 18425781, 26310554), 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.
Integrated Genetics/Laboratory Corporation of America RCV000792061 SCV001337997 pathogenic Glycogen storage disease, type II 2020-01-30 criteria provided, single submitter clinical testing Variant summary: GAA c.2105G>T (p.Arg702Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 222484 control chromosomes (gnomAD). c.2105G>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; examples Bali_2012, Stenger_2015, Broomfield_2016, Reuser_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity in vitro (Kroos_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was 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.