ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.877G>A (p.Gly293Arg) (rs121907945)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics,Klinikum rechts der Isar RCV000578430 SCV000680242 pathogenic Glycogen storage disease, type II 2017-11-16 criteria provided, single submitter clinical testing
Invitae RCV000578430 SCV000825724 pathogenic Glycogen storage disease, type II 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 293 of the GAA protein (p.Gly293Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121907945, ExAC 0.01%). This variant has been observed in individuals with low alpha-glucosidase enzyme activity (less than 40% of normal), findings that are highly specific for glycogen storage disease type II (PMID: 24590251, 22676651). This variant has been observed to be homozygous or in combination with another GAA variant in individuals affected with glycogen storage disease type II (PMID: 14695532, 27344650, 29181627, 18607768, 17573812, 29122469, 15668445). ClinVar contains an entry for this variant (Variation ID: 4036). Experimental studies have shown that this missense change results in a GAA protein with severely reduced enzymatic activity (PMID: 14695532, 19862843). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728952 SCV000856579 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000578430 SCV001361534 pathogenic Glycogen storage disease, type II 2019-07-05 criteria provided, single submitter clinical testing Variant summary: GAA c.877G>A (p.Gly293Arg) results in a non-conservative amino acid change located in the N-terminal domain (IPR025887) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245436 control chromosomes (gnomAD). c.877G>A has been reported in the literature in several compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Muller-Felber_2007, Angelini_2012, Herzog_2012). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a less 10% of normal enzyme activity for the variant protein (Hermans_2004, Flanagan_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of these laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004251 SCV000024417 pathogenic Glycogen storage disease II, adult form 2005-01-25 no assertion criteria provided literature only
Broad Institute Rare Disease Group,Broad Institute RCV000578430 SCV001422611 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly293Arg variant in GAA has been reported in 8 individuals (including 2 Germans, 2 from the UK, 1 Italian, and 1 Afghan individuals) with Glycogen Storage Disease II (PMID: 14695532, 18429042, 23566438, 15668445, 18607768, 26497565), and has also been reported pathogenic by Invitae, EGL Genetic Diagnostics, OMIM, and Klinikum rechts der Isar in ClinVar (Variation ID: 4036). This variant has been identified in 0.006% (2/35062) of Latino chromosomes, 0.004% (1/24260) of European (non-Finnish) chromosomes, and 0.004% (1/24388) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907945). 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 provide some evidence that the p.Gly293Arg variant may impact GAA activity and levels (PMID: 14695532, 19862843). 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 reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly293Arg variant is pathogenic (PMID: 26497565, 23566438). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low levels of GAA activity in leukocytes, muscle, or lymphocytes (PMID: PMID: 26497565, 23566438). 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 the variant and multiple occurrences with reported pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PP4, PM2, PP3 (Richards 2015).

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