ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1933G>A (p.Asp645Asn) (rs368438393)

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
Counsyl RCV000169030 SCV000220179 likely pathogenic Glycogen storage disease, type II 2014-03-21 criteria provided, single submitter literature only
GeneDx RCV000483035 SCV000568677 pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing The D645N pathogenic variant in the GAA gene has been previously reported, in both the compound heterozygous and homozygous state, in patients with infantile GSDII (Huie et al., 1998; Del Rizzo et al., 2010). Functional studies demonstrate D645N results in significantly reduced GAA enzyme activity compared to wild type controls (Huie et al., 1998). The D645N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and different missense variants at the same position (D645H/Y/E) have been previously reported in association with GSDII (Lin et al., 1995; Gort et al., 2007; Hermans et al., 1993). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000169030 SCV000915789 pathogenic Glycogen storage disease, type II 2017-05-10 criteria provided, single submitter clinical testing The GAA c.1933G>A (p.Asp645Asn) variant has been reported in six studies and is found in a total of seven patients with infantile-onset Pompe disease (also known as glycogen storage disease, type II). The p.Asp645Asn variant was present in five patients in a compound heterozygous state and two patients in a homozygous state (Huie et al. 1998; Kroos et al. 2004; McCready et al. 2007; Pittis et al. 2008; Del Rizzo et al. 2010; Tan et al. 2015). In addition, two unaffected parents carried the variant in a heterozygous state (Kroos et al. 2004; Tan et al. 2015). Control data are unavailable for the p.Asp645Asn variant, which is reported at a frequency of 0.00023 in the African population of the Exome Sequencing Project, but this is based on one allele in a region of low sequence coverage. In vitro expression of the p.Asp645Asn variant in both SV40 immortalized fibroblasts (TR4912) and COS cells yielded low enzyme activity (Huie et al. 1998; Kroos et al. 2004). Based on the collective evidence, the p.Asp645Asn variant is classified as pathogenic for glycogen storage disease, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000169030 SCV000917400 pathogenic Glycogen storage disease, type II 2018-12-10 criteria provided, single submitter clinical testing Variant summary: GAA c.1933G>A (p.Asp645Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 86510 control chromosomes (ExAC). c.1933G>A has been reported in the literature in compound heterozygous or homozygous state in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Huie 1998, Prater 2012, McCready 2007). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Huie 1998, Prater 2012, McCready 2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169030 SCV000820187 pathogenic Glycogen storage disease, type II 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 645 of the GAA protein (p.Asp645Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs368438393, ExAC 0.01%). This variant has been reported in individuals affected with Pompe disease, including several who are homozygous for this variant (PMID: 9535769, 15145338, 17723315, 18429042, 20830524, 23787031). ClinVar contains an entry for this variant (Variation ID: 188728). Experimental studies have shown that this missense change disrupts GAA enzyme activity in cell culture (PMID: 9535769, 15145338), and cells derived from individuals who carry this variant have been reported to have very low residual enzyme activity (PMID: 9535769, 15145338, 17723315, 20830524). 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.