ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1927G>A (p.Gly643Arg) (rs28937909)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409137 SCV000485382 pathogenic Glycogen storage disease, type II 2016-09-09 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000788193 SCV000927226 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing
Invitae RCV000409137 SCV000937212 pathogenic Glycogen storage disease, type II 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 643 of the GAA protein (p.Gly643Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs28937909, ExAC 0.009%). This variant has been observed in several individuals affected with Pompe disease. (PMID: 8401535, 24158270,18607768). ClinVar contains an entry for this variant (Variation ID: 4023). This variant has been reported to disrupt GAA protein function (PMID: 8401535). 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.
Mendelics RCV000409137 SCV001140842 pathogenic Glycogen storage disease, type II 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000409137 SCV001338528 pathogenic Glycogen storage disease, type II 2020-04-17 criteria provided, single submitter clinical testing Variant summary: GAA c.1927G>A (p.Gly643Arg) results in a non-conservative amino acid change in 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 2.5e-05 in 242074 control chromosomes. c.1927G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; eg. Hermans_1993, Laforet_2000, McCready_2007, Oba-Shinjo_2009, Pittis_2008). Experimental evidence has shown the variant to result in impairment of intracellular transport and maturation of the protein, resulting in severe enzyme deficiency (Hermans_1993) Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004238 SCV000024404 pathogenic Glycogen storage disease II, adult form 1993-01-01 no assertion criteria provided literature only
Broad Institute Rare Disease Group,Broad Institute RCV000409137 SCV001423065 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly643Arg variant in GAA has been reported in the homozygous and heterozygous state in at least 31 individuals (including 8 Italian, 7 French, 3 Brazilian, 1 German, 1 from the UK, 1 Argentinian, 1 Canadian, and 1 Saudi Arabian individuals) with Glycogen Storage Disease II (PMID: 30023291, 25052852, 17056254, 25783438, 30155607, 26349193, 11071489, 20559845, 26497565, 19588081, 18607768, 19862843, 18429042, 17723315, 16917947, 9521422, 8401535), and has also been reported pathogenic by Invitae, Counsyl, Blueprint Genetics, and OMIM in ClinVar (Variation ID: 4023). This variant has been identified in 0.004% (4/109080) of European (non-Finnish) chromosomes, 0.003% (1/29618) of South Asian chromosomes, and 0.003% (1/33956) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28937909). 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 the variant and structural analysis provide some evidence that the p.Gly643Arg variant may impact the GAA active site, GAA processing, and GAA activity (PMID: 19862843, 9521422, 8401535, 25103075). 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 and in combination with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly643Arg variant is pathogenic (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). 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, and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015).

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