ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1441T>C (p.Trp481Arg) (rs772883420)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169391 SCV000220783 likely pathogenic Glycogen storage disease, type II 2014-10-10 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169391 SCV000919383 pathogenic Glycogen storage disease, type II 2018-06-22 criteria provided, single submitter clinical testing Variant summary: GAA c.1441T>C (p.Trp481Arg) 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 allele was found at a frequency of 2.2e-05 in 276888 control chromosomes. c.1441T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), with reported severely deficient GAA enzyme activity (Tsai_2017, Hermans_2004, Herzog_2012, Raben_1998, van Capelle2016). These data indicate that the variant is likely to be associated with disease. 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 pathogenic.
Invitae RCV000169391 SCV000956690 pathogenic Glycogen storage disease, type II 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 481 of the GAA protein (p.Trp481Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs772883420, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Pompe disease (PMID: 18757064, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in combination with another GAA variant in individuals affected with Pompe disease (PMID: 10189220, 14695532, 22676651). ClinVar contains an entry for this variant (Variation ID: 189007). Experimental studies have shown that this missense change results in a GAA protein with residual enzyme activity (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169391 SCV001422626 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp481Arg variant in GAA has been reported in 6 individuals (including 1 African American and 1 German individuals) with Glycogen Storage Disease II (PMID: 27189384, 18757064, 10189220, 19862843, 26497565, 22676651, 14695532, 28657663), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 189007). This variant has been identified in 0.008% (2/24904) of African chromosomes and 0.003% (4/128730) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772883420). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp481Arg variant may impact ligand binding and GAA activity but not GAA levels (PMID: 19862843, 14695532, 15501829). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp481Arg variant is pathogenic (PMID: 26497565, 22676651, 27189384, 28657663). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on very low GAA activity in assays with relevant tissue (PMID: 26497565, 22676651, 27189384, 28657663). In summary, this variant meets criteria to be classified as pathogenic for p.Trp481Arg in an autosomal recessive manner based on in vitro functional evidence and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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.