ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1799G>A (p.Arg600His) (rs377544304)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521900 SCV000617644 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing The R600H pathogenic variant in the GAA gene has been previously reported in multiple unrelated individuals with GSDII, who harbored a pathogenic variant on the opposite GAA allele (Ko et al., 1999; van der Beek et al., 2008). Analysis of R600H transfected COS-7 cells demonstrates less than 2% residual GAA enzyme activity compared to wildtype controls (Flanagan et al., 2009). The R600H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and different missense variants at the same position (R600C/L) have been previously reported in the homozygous and compound heterozygous state in individuals with GSDII (Tsujino et al., 2000; McCready et al., 2007). Additionally, the majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Counsyl RCV000408964 SCV000485365 likely pathogenic Glycogen storage disease, type II 2015-11-24 no assertion criteria provided clinical testing
Laboratorio de Medicina Genomica, Hospital General de Culiacan RCV000408964 SCV000680488 pathogenic Glycogen storage disease, type II no assertion criteria provided clinical testing The observed phenotype is merely musculoskeletal. Dyspnea on exertion, difficulty in both genuflection and climbing stairs, progressive muscle weakness in pelvic area, amyotrophy, hyperflexia, early fatigue, myalgias and cramps, Gowers sign were observed in all siblings, while weakness in arms, scapula alata and progresive muscle weakness in scapula area were observed in males only.
Broad Institute Rare Disease Group,Broad Institute RCV000408964 SCV001423118 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg600His variant in GAA has been reported in at least 12 individuals in the compound heterozygous state with Glycogen Storage Disease II (PMID: 22676651, 21920843, 18757064, 27649523, 24715333, 18995995, 10338092, 27649523, 15121988). This variant has also been reported pathogenic by GeneDx and Laboratorio de Medicina Genomica and likely pathogenic by Counsyl in ClinVar (Variation ID: 370130). This variant has been identified in 0.003% (1/30606) of South Asian chromosomes and 0.002% (2/111734) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377544304). 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 and HEK cells transfected with this variant provide some evidence that the p.Arg600His variant may impact enzyme levels and activity (PMID: 19862843, 24715333). 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 pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg600His variant is pathogenic (PMID: 27649523, 22676651, 24715333). The phenotype of individuals heterozygous with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays (PMID: 24715333, 27649523, 15121988). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600Cys, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 14643388, 24384324, 18458862, 14695532, 11053688, 21982629). 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 and multiple occurrences with variants reported in association with disease in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015).

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