ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2237G>A (p.Trp746Ter) (rs752921215)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000302789 SCV000329853 pathogenic not provided 2016-06-08 criteria provided, single submitter clinical testing The W746X pathogenic variant in the GAA gene has been previously reported multiple times in association with both infantile-onset and late-onset GSDII (Beesley et al., 1998; Montalvo et al., 2006; Pittis et al., 2008). Clinical variability was described amongst individuals harboring the W746X variant and GAA enzyme activity ranged from decreased to absent (Montalvo et al., 2006; Remiche et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W746X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Genetic Services Laboratory, University of Chicago RCV000501120 SCV000594901 pathogenic Glycogen storage disease, type II 2016-05-23 criteria provided, single submitter clinical testing
Invitae RCV000501120 SCV000752063 pathogenic Glycogen storage disease, type II 2018-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp746*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752921215, ExAC 0.002%). This variant has been reported in several individuals affected with Pompe disease (PMID: 25488666, 10206684, 24158270). ClinVar contains an entry for this variant (Variation ID: 280063). Loss-of-function variants in GAA are known to be pathogenic (PMID: 2252923, 18425781). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000302789 SCV000861727 pathogenic not provided 2018-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000501120 SCV000917394 pathogenic Glycogen storage disease, type II 2018-08-13 criteria provided, single submitter clinical testing Variant summary: GAA c.2237G>A (p.Trp746X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2560C>T, p.Arg854*). The variant allele was found at a frequency of 8.1e-06 in 245810 control chromosomes (gnomAD). c.2237G>A has been reported in the literature in multiple individuals affected with Late Onset Pompe Disease (Montalvo_2006, Liu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

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