ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.32G>A (p.Arg11Gln) (rs138812846)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000250396 SCV000302687 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724696 SCV000331867 uncertain significance not provided 2015-10-07 criteria provided, single submitter clinical testing
Invitae RCV000525907 SCV000626605 uncertain significance Glycogen storage disease, type II 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 11 of the GAA protein (p.Arg11Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138812846, ExAC 0.1%). This variant has been reported in an individual referred for Pompe testing (PMID: 18425781). ClinVar contains an entry for this variant (Variation ID: 255362). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000724696 SCV000716344 likely benign not provided 2020-09-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18425781, 31301153)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000250396 SCV000919371 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: GAA c.32G>A (p.Arg11Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 275638 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00014 vs 0.0042), allowing no conclusion about variant significance. The variant, c.32G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2008) but was classified as not pathogenic by the authors. These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kroos_2008). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x1, uncertain significance 2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Nilou-Genome Lab RCV000525907 SCV001810613 uncertain significance Glycogen storage disease, type II 2021-07-22 criteria provided, single submitter clinical testing

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