ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1099T>C (p.Trp367Arg) (rs1555600061)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671718 SCV000796724 uncertain significance Glycogen storage disease, type II 2017-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000671718 SCV000917395 pathogenic Glycogen storage disease, type II 2018-09-10 criteria provided, single submitter clinical testing Variant summary: GAA c.1099T>C (p.Trp367Arg) 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 244902 control chromosomes (gnomAD). c.1099T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), including a homozygous patient (Palmer 2007, Palermo 2012, Musumeci 2012, Mori 2017). These data indicate that the variant is likely to be associated with disease. One of these publications also reported that GAA enzyme activity levels measured from a dried blood spot were outside the range of normal activity in a homozygous patient (Palmer 2007). At least one other publication reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <2% of normal activity (Flanagan 2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000671718 SCV001578522 pathogenic Glycogen storage disease, type II 2020-02-22 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 367 of the GAA protein (p.Trp367Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Pompe disease (PMID: 17056254, 23787031, 22958975, 31510962). 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: 555820). This variant has been reported to affect GAA protein function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic.

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