ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1935C>A (p.Asp645Glu) (rs28940868)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000055768 SCV000752045 pathogenic Glycogen storage disease, type II 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 645 of the GAA protein (p.Asp645Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs28940868, ExAC 0.2%). This variant has been reported to be a common cause of glycogen storage disease type II in China, Taiwan and Thailand, although it has also been found in other populations (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). ClinVar contains an entry for this variant (Variation ID: 4029). Experimental studies have shown that this missense change reduces GAA enzymatic activity (PMID: 8094613). A different missense substitution at this codon (p.Asp645Asn) has been determined to be pathogenic (PMID: 9535769, 15145338, 17723315, 20830524). This suggests that the aspartic acid residue is critical for GAA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000055768 SCV000807221 pathogenic Glycogen storage disease, type II 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 1-year-old female with infantile Pompe disease
Integrated Genetics/Laboratory Corporation of America RCV000055768 SCV000919370 pathogenic Glycogen storage disease, type II 2018-02-08 criteria provided, single submitter clinical testing Variant summary: GAA c.1935C>A (p.Asp645Glu) 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 0.00012 in 269490 control chromosomes. c.1935C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. This variant has been reported to be one of the most common mutations among Chinese patients with Pompe disease, suggesing a founder effect. At least one publication reports experimental evidence evaluating an impact on protein function resulting in 10%-<30% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan University RCV000055768 SCV001190560 pathogenic Glycogen storage disease, type II 2019-05-10 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000055768 SCV001193876 pathogenic Glycogen storage disease, type II 2019-12-20 criteria provided, single submitter clinical testing NM_000152.3(GAA):c.1935C>A(D645E) is classified as pathogenic in the context of Pompe disease and is associated with the infantile-onset form of this disease. Sources cited for classification include the following: PMID 8094613, 21232767, 16702877, 21039225 and 10338092. Classification of NM_000152.3(GAA):c.1935C>A(D645E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
OMIM RCV000004244 SCV000024410 pathogenic Glycogen storage disease type II, infantile 1998-01-01 no assertion criteria provided literature only
GeneReviews RCV000055768 SCV000086726 pathologic Glycogen storage disease, type II 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000055768 SCV001422758 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Asp645Glu variant in GAA has been reported in at least 48 individuals (including 42 individuals from China or Taiwan and 5 individuals from Thailand) with Glycogen Storage Disease II (PMID: 8094613, 21039225, 21232767, 10338092, 9554747), and has also been reported pathogenic by Counsyl, Invitae, Baylor Genetics, OMIM, and GeneReviews in ClinVar (Variation ID: 4029). This variant has been identified in 0.173% (34/19660) of East Asian chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs28940868). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Asp645Glu variant may impact protein function (PMID: 8094613, 8935410). 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 the homozygous state and with reported pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp645Glu variant is pathogenic (PMID: 9554747, 8094613). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in fibroblasts, consistent with disease (PMID: 9554747, 8094613). Three additional variants at the same position, (p.Asp645Asn, p.Asp645His, and p.Asp645Tyr), have been reported pathogenic or likely pathogenic in association with Glycogen Storage Disease II in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 188728, 556386, 189013). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II, multiple pathogenic or likely pathogenic variants reported at the same position, and in vitro functional studies with COS cells transfected with this variant. ACMG/AMP Criteria applied: PM3_Strong, PM5_Strong, PS3, PP3, PP4 (Richards 2015).

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