ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2560C>T (p.Arg854Ter) (rs121907943)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255539 SCV000321686 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The R854X pathogenic variant in the GAA gene has been reported previously in multiple individualswith glycogen storage disease type II in the homozygous state, as well as in the heterozygous state inthe presence of a second GAA variant (Bernstein et al., 2010; Burrow et al., 2010; Abbott et al., 2011;Palermo et al., 2012). Additionally, functional studies in COS cells with the R854X variant show thatthis variant impacts the function of the protein (Hermans et al., 1993). This variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNAdecay. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Projectreports that R854X was observed in 0.23%, 10/4406 alleles, from individuals of African Americanbackground, indicating it may be a rare variant in this population. We interpret R854X as apathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255539 SCV000331031 pathogenic not provided 2017-12-20 criteria provided, single submitter clinical testing
Invitae RCV000004249 SCV000626581 pathogenic Glycogen storage disease, type II 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 854 (p.Arg854*) of the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic. This particular variant has been reported as homozygous and as compound heterozygous in multiple individuals affected with glycogen storage disease type II (PMID: 9529346, 19588081, 17723315). ClinVar contains an entry for this variant (Variation ID: 4034). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000004249 SCV000695654 pathogenic Glycogen storage disease, type II 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The GAA c.2560C>T (p.Arg854X) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 25/116512 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.002243 (23/10254). These frequencies are lower than the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), but suggest that this variant is of African origin. The variant has been identified in homozygous and compound heterozygous state in patients with Pompe disease, suggesting the variant is causative. Additionally, functional studies indicate that the variant has negligible catalytic activity and that the variant results in a transcript that is either not expressed or unstable. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000004249 SCV000893478 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000004249 SCV000024415 pathogenic Glycogen storage disease, type II 1998-04-01 no assertion criteria provided literature only
GeneReviews RCV000004249 SCV000086728 pathologic Glycogen storage disease, type II 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000004249 SCV000485153 pathogenic Glycogen storage disease, type II 2016-03-08 no assertion criteria provided clinical testing

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