ClinVar Miner

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

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Total submissions: 3
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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.

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