ClinVar Miner

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

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Total submissions: 7
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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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000408964 SCV001472312 pathogenic Glycogen storage disease, type II 2019-10-18 criteria provided, single submitter clinical testing The GAA c.1799G>A; p.Arg600His variant (rs377544304) is reported in the literature in multiple individuals affected with glycogen storage disease type II, also known as Pompe disease, each of whom also carried a second pathogenic variant (de Vries 2011, Ko 1999, van der Beek 2008). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 370130), and it is found on only three chromosomes in the Genome Aggregation Database (3/248322 alleles), indicating it is not a common polymorphism. The arginine at codon 600 is highly conserved, and functional characterization of the variant protein expressed in cultured cells suggests it has less than 2% of wildtype activity (Flanagan 2009). Additionally, other amino acid substitutions at this codon (p.Arg600Cys, p.Arg600Leu) have been reported in individuals with Pompe disease and are considered disease-causing (Fukuhara 2017, McCready 2007). Based on available information, the p.Arg600His variant is considered to be pathogenic. References: de Vries JM et al. First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease. Mol Genet Metab. 2011 Dec;104(4):552-5. Flanagan JJ et al. The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase. Hum Mutat. 2009 Dec;30(12):1683-92. Fukuhara Y et al. A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. Mol Genet Metab Rep. 2017 Oct 31;14:3-9. Ko et al. Molecular genetic study of Pompe disease in Chinese patients in Taiwan. Hum Mutat. 1999;13(5):380-4. McCready ME et al. Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. Mol Genet Metab. 2007 Dec;92(4):325-35. van der Beek NA et al. Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities. J Neurol Sci. 2008 Dec 15;275(1-2):46-50.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000408964 SCV001482247 pathogenic Glycogen storage disease, type II 2021-02-14 criteria provided, single submitter clinical testing Variant summary: GAA c.1799G>A (p.Arg600His) 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 1.2e-05 in 248322 control chromosomes. c.1799G>A has been reported in the literature in multiple individuals affected with classic infantile, childhood, or adult forms of CRIM positive Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Ko_1999, de Vries_2011, Monies_2019, Pompe disease variant database). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained in the context of this evaluation. 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 (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000408964 SCV001585654 pathogenic Glycogen storage disease, type II 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 600 of the GAA protein (p.Arg600His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs377544304, ExAC 0.002%). This variant has been observed in individual(s) with Pompe disease (PMID: 10338092, 20033296, 31342611, 30155607). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370130). This variant has been reported to affect GAA protein function (PMID: 19862843). This variant disrupts the p.Arg600 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338092, 21039225, 21232767, 21439876). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
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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