ClinVar Miner

Submissions for variant NM_000152.3(GAA):c.2561G>A (p.Arg854Gln) (rs149968110)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000275982 SCV000339549 likely benign not specified 2018-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000586838 SCV000779729 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the GAA gene. The R854Q variant has not been published as pathogenic or been reported as benign to our knowledge. R854Q has been observed in 63/9576 (0.7%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, though no individuals were reported to be homozygous (Lek et al., 2016). The R854Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the GAA gene has a low rate of benign missense variation, and missense variants are a common mechanism of disease for this gene (Stenson et al., 2014).
Integrated Genetics/Laboratory Corporation of America RCV000586838 SCV000695655 uncertain significance not provided 2016-01-14 criteria provided, single submitter clinical testing Variant summary: GAA c.2561G>A affects a non-conserved nucleotide, resulting in amino acid change from Arg to Gln. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 32/116434 control chromosomes at a frequency of 0.0002748, which does not significantly exceed maximal expected frequency of a pathogenic GAA allele (0.0042205). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000535402 SCV000626583 uncertain significance Glycogen storage disease, type II 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 854 of the GAA protein (p.Arg854Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149968110, ExAC 0.04%) but has not been reported in the literature in individuals with a GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 286210). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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