ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2104C>T (p.Arg702Cys) (rs786204645)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169431 SCV000220843 likely pathogenic Glycogen storage disease, type II 2014-10-28 criteria provided, single submitter literature only
Invitae RCV000169431 SCV000942734 pathogenic Glycogen storage disease, type II 2020-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 702 of the GAA protein (p.Arg702Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with findings that are highly specific for GAA-related conditions (PMID: 14972326, 24158270). ClinVar contains an entry for this variant (Variation ID: 189040). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 14972326, 19862843). This variant disrupts the p.Arg702 acid residue in GAA. Other variants that disrupt this residue have been observed in affected individuals (PMID: 18211760, 18425781, 26310554), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090261 SCV001245693 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169431 SCV001623257 pathogenic Glycogen storage disease, type II 2021-05-03 criteria provided, single submitter clinical testing Variant summary: GAA c.2104C>T (p.Arg702Cys) 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 was absent in 222816 control chromosomes. c.2104C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Montalvo_2004, Angelini_2012, Chen_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Montalvo_2004). Three 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.
Broad Institute Rare Disease Group, Broad Institute RCV000169431 SCV001422657 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg702Cys variant in GAA has been reported in 5 individuals (including 1 from Italy and 1 from France) with Glycogen Storage Disease II (PMID: 14972326, 25786784, 16917947, 24158270, 22704482) and has been identified in 0.011% (1/8702) of African chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs786204645). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported likely pathogenic by Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 189040). In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Arg702Cys variant may impact GAA activity (PMID: 14972326, 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.Arg702Cys variant is pathogenic (PMID: 24158270, 22704482, 14972326). Two additional variants at the the same position, p.Arg702His and p.Arg702Leu, have been reported likely pathogenic in association with disease in ClinVar (Variation ID: 426278, 92472). The phenotype of individuals heterozygous with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays with relevant tissue (PMID: 24158270, 22704482, 14972326). 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, PM2, PP3, PP4 (Richards 2015).

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