ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.854C>G (p.Pro285Arg) (rs764622267)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210587 SCV000263032 pathogenic Inborn genetic diseases 2014-10-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000797884 SCV000937469 uncertain significance Glycogen storage disease, type II 2019-01-04 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 285 of the GAA protein (p.Pro285Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GAA variant in an individual affected with Pompe disease (PMID: 14695532). ClinVar contains an entry for this variant (Variation ID: 225114). This variant has been reported to affect GAA protein function (PMID: 14695532, 19862843). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Institute Rare Disease Group,Broad Institute RCV000797884 SCV001423075 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Pro285Arg variant in GAA has been reported in at least 3 individuals (including 1 German individual) with Glycogen Storage Disease II (PMID: 14695532, 12213618, 28196920; DOI: 10.1016/S1472-6483(16)30370-4), and has also been reported pathogenic by Ambry Genetics and as a VUS by Invitae in ClinVar (Variation ID: 225114). This variant has been identified in 0.001% (1/87084) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764622267). 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.Pro285Arg variant may impact GAA activity (PMID: 14695532, 19862843, 12213618). 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 a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Pro285Arg variant is pathogenic (PMID: 14695532, 12213618). One pathogenic variant at the same position, p.Pro285Ser, has been reported in association with Glycogen Storage Disease II (Variation ID: 281052). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity in their leukocytes or fibroblasts and no known pseudodeficiency alleles in at least one individual (PMID: 28196920, 12213618). 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 with COS cells transfected with this variant, individuals with phenotypes highly specific for Glycogen Storage Disease II, and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PP4_Moderate, PM3_Supporting, PM2, PP3 (Richards 2015).

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