ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1933G>C (p.Asp645His) (rs368438393)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169400 SCV000220797 likely pathogenic Glycogen storage disease, type II 2014-10-14 criteria provided, single submitter literature only
Invitae RCV000169400 SCV001228299 pathogenic Glycogen storage disease, type II 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 645 of the GAA protein (p.Asp645His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs368438393, ExAC 0.01%). This variant has been observed in individuals affected with infantile Pompe disease (PMID: 7695647, 12897283). ClinVar contains an entry for this variant (Variation ID: 189013). This variant has been reported to affect GAA protein function (PMID: 7695647). This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 9535769, 15145338, 21039225, 21439876, 24269976), 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.
Broad Institute Rare Disease Group,Broad Institute RCV000169400 SCV001422907 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Asp645His variant in GAA has been reported in two individuals from Taiwan with Glycogen Storage Disease II (PMID: 12897283, 7695647), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 189013). This variant has been identified in 0.006% (1/18070) of East Asian chromosomes and 0.005% (1/20588) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). 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 with COS cells transfected with this variant provide some evidence that the p.Asp645His variant may impact GAA activity, but not GAA levels (PMID: 19862843, 7695647). 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 in two individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp645His variant is pathogenic (PMID: 12897283, 7695647). Three additional variants at the the same position (p.Asp645Tyr, p.Asp645Asn, p.Asp645Glu), including 2 pathogenic variants curated by our study, have been reported in association with disease in ClinVar, suggesting that a change at this position may not be tolerated (Variation ID: 556386, 188728, 4029). The phenotype of two individuals homozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected by assays with fibroblast cells (PMID: 7695647, 12897283). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences of pathogenic missense variants at the same position. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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