ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1124G>T (p.Arg375Leu) (rs142752477)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725236 SCV000335210 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Counsyl RCV000306541 SCV000486956 likely pathogenic Glycogen storage disease, type II 2016-09-13 criteria provided, single submitter clinical testing
Invitae RCV000306541 SCV001212310 pathogenic Glycogen storage disease, type II 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 375 of the GAA protein (p.Arg375Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs142752477, ExAC 0.002%). This variant has been observed in several individuals affected with Pompe disease (PMID: 18429042, 29422078, 24158270, 22990675). ClinVar contains an entry for this variant (Variation ID: 283230). This variant has been reported to affect GAA protein function (PMID: 18429042). This variant disrupts the p.Arg375 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21757382), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000306541 SCV001422909 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg375Leu variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22081099, 24158270, 25103075, 25396301, 18429042) and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 283230). This variant has been identified in 0.002% (2/111942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs142752477). 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 a GAA-deficient human fibroblast cell line provide some evidence that the p.Arg375Leu variant may impact GAA production and activity (PMID: 18429042). 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 2 pathogenic variants curated by our study in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Arg375Leu variant is pathogenic (PMID: 22081099, 24158270, 25103075, 25396301, 18429042). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity in muscle tissue <10% of normal, consistent with disease (PMID: 24158270, 22081099). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Supporting, PM2, PP3, PP4 (Richards 2015).

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