ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.925G>A (p.Gly309Arg) (rs543300039)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169127 SCV000220337 likely pathogenic Glycogen storage disease, type II 2014-05-22 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723463 SCV000700458 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169127 SCV000919381 pathogenic Glycogen storage disease, type II 2018-05-24 criteria provided, single submitter clinical testing Variant summary: GAA c.925G>A (p.Gly309Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 108582 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.925G>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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169127 SCV000938984 pathogenic Glycogen storage disease, type II 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 309 of the GAA protein (p.Gly309Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs543300039, ExAC 0.02%). This variant has been observed as homozygous or in combination with another GAA variant in several individuals affected with Pompe disease (PMID: 9660056, 17616415, 29122469, 17210890, 23601496, 24495340, 16917947, 24245577). ClinVar contains an entry for this variant (Variation ID: 188797). Experimental studies have shown that this missense change leads to the production of non-functional alpha-glucosidase enzyme in vitro (PMID: 9660056). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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