ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.569G>A (p.Arg190His) (rs528367092)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169143 SCV000220363 likely pathogenic Glycogen storage disease, type II 2014-05-31 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169143 SCV000919379 pathogenic Glycogen storage disease, type II 2018-04-02 criteria provided, single submitter clinical testing Variant summary: GAA c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 1.6e-05 in 244686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.6e-05 vs 0.0042), allowing no conclusion about variant significance. The variant, c.569G>A, 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. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. 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.
Invitae RCV000169143 SCV001226092 likely pathogenic Glycogen storage disease, type II 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 190 of the GAA protein (p.Arg190His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs528367092, ExAC 0.01%). This variant has been observed in several individuals affected with Pompe disease (PMID: 23000108, 24444888, 21484825, 29149851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg190 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 29046207), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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