ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs786204645
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Total submissions: 11
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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 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 702 of the GAA protein (p.Arg702Cys). This variant is present in population databases (rs786204645, gnomAD 0.005%). This missense change has been observed in individual(s) with findings that are highly specific for GAA-related conditions (PMID: 14972326, 24158270). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 14972326, 19862843). This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18211760, 18425781, 26310554). 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.
CeGaT Center for Human Genetics Tuebingen RCV001090261 SCV001245693 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000169431 SCV001422657 pathogenic Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter 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, http://gnomad.broadinstitute.org; 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).
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.
Revvity Omics, Revvity Omics RCV001090261 SCV002023812 pathogenic not provided 2023-12-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001090261 SCV002065876 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing The second sequence change is a missense variant in exon 15, c.2104C>T (p.Arg702Cys). The p.Arg702Cys change affects a highly conserved amino acid residue located in a domain of the GAA protein that is known to be functional. The p.Arg702Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database in one heterozygous individual which corresponds to a population frequency of 0.00039% (dpSNP rs786204645). This sequence change has been reported in individuals with glycogen storage disease II in the homozygous state and in the compound heterozygous state with other variants classified as pathogenic including the c.-32-13T>G sequence change (PMID: 34020684, 27858611, 24158270, 31086307, 14972326). Additionally, other sequence changes that affect this same amino acid have been reported in individuals with GAA-related disorders (18211760, 18425781, 26310554). Experimental studies have shown that this sequence change impacts the function of the GAA protein (PMID: 14972326, 19862843). Based on these collective evidences, the c.2104C> variant is classified as pathogenic.
MGZ Medical Genetics Center RCV000169431 SCV002579605 pathogenic Glycogen storage disease, type II 2021-11-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000169431 SCV002809772 pathogenic Glycogen storage disease, type II 2021-08-24 criteria provided, single submitter clinical testing
GeneDx RCV001090261 SCV003798876 pathogenic not provided 2023-01-30 criteria provided, single submitter clinical testing Functional analysis found this variant is associated with significantly reduced enzyme activity compared to wild-type (Montalvo AL et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31254424, 31086307, 24158270, 14972326, 29046207, 32959227, 28856460, 31342611, 30922962, 25786784, 16917947, 31392188, 33301762, 34530085, 18425781)
Baylor Genetics RCV000169431 SCV004197843 pathogenic Glycogen storage disease, type II 2023-04-22 criteria provided, single submitter clinical testing

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