ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2173C>T (p.Arg725Trp) (rs121907938)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169045 SCV000695648 pathogenic Glycogen storage disease, type II 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The GAA c.2173C>T (p.Arg725Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/44258 control chromosomes at a frequency of 0.0000226, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in at least 5 patients with Pompe disease (3 juvenile and 2 adult). Functional studies showed GAA p.R725W had less than 10% residual activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169045 SCV000939765 pathogenic Glycogen storage disease, type II 2020-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 725 of the GAA protein (p.Arg725Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121907938, ExAC 0.004%). This variant has been observed in combination with another GAA variant in several individuals affected with Pompe disease (PMID: 8401535, 17616415, 19588081, 21550241, 28648663). ClinVar contains an entry for this variant (Variation ID: 4024). This variant has been reported to reduce GAA enzyme activity in vitro (PMID: 8401535, 21972175). This variant disrupts the p.Arg725 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related disease (PMID: 18458862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001569366 SCV001793430 pathogenic not provided 2021-02-25 criteria provided, single submitter clinical testing Reported in ClinVar as pathogenic or likely pathogenic by other clinical laboratories (ClinVar Variant ID#4024; Landrum et al., 2016); Published functional studies demonstrate reduced enzyme activity (Hermans et al., 1993; Ebrahim et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 22252923, 27711114, 31254424, 31342611, 21550241, 19588081, 17616415, 8401535, 21972175, 28648663)
OMIM RCV000004239 SCV000024405 pathogenic Glycogen storage disease II, adult form 1993-01-01 no assertion criteria provided literature only
Counsyl RCV000169045 SCV000220203 pathogenic Glycogen storage disease, type II 2018-09-07 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000169045 SCV001422653 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Arg725Trp variant in GAA has been reported in 6 individuals (including 3 Spanish and 1 Brazilian individuals) in the compound heterozygous state with Glycogen Storage Disease II (PMID: 21550241, 8401535, 17616415, 19588081). This variant has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics, Invitae, and OMIM in ClinVar (Variation ID: 4024). This variant has been identified in 0.077% (7/9058) of Ashkenazi Jewish chromosomes and 0.002% (2/104918) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs121907938). 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 HEK and COS cells provide some evidence that the p.Arg725Trp variant may impact GAA activity (PMID: 21972175, 8401535). 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 confirmed in trans with a pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg725Trp variant is pathogenic (PMID: 8401535). The phenotype of heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in relevant tissues (PMID: 17616415, 8401535, 21550241). 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 transfected cells and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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