ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1978C>T (p.Arg660Cys) (rs759518659)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674901 SCV000800311 likely pathogenic Glycogen storage disease, type II 2018-05-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000674901 SCV000919375 pathogenic Glycogen storage disease, type II 2018-02-08 criteria provided, single submitter clinical testing Variant summary: GAA c.1978C>T (p.Arg660Cys) results in a non-conservative amino acid change located in the Catalytic GH31 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity, potentially, due to the change affecting maturation process (Flanagan_2009; Palmer_2007). The variant allele was found at a frequency of 1.1e-05 in 1/91962 control chromosomes in ExAC dataset. The c.1978C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. In addition, another alteration of the same codon, R660H, has been reported as "Pathogenic" for Pompe disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000674901 SCV001422968 pathogenic Glycogen storage disease, type II 2020-01-14 no assertion criteria provided curation The p.Arg660Cys variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 29124014, 17056254) and has been identified in 0.006% (1/18006) of East Asian chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759518659). 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 on ClinVar as Likely Pathogenic by Counsyl and Pathogenic by Integrated Genetics (VariationID: 558604). In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Arg660Cys variant may impact protein function (PMID: 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg660His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 14643388, 19862843, 22658377, 20638881, 20472203, 21484825; Variation ID: 189172). Additionally, this variant has been reported in combination with likely pathogenic variant p.Val466Gly and in an individual with glycogen storage disease II (PMID: 17056254). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on reduced GAA activity in lymphocytes and muscle tissue from affected individuals (PMID: 17056254, 29124014). 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 studies demonstrating an impact on protein function and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PP4 (Richards 2015).

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