ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1548G>A (p.Trp516Ter) (rs140826989)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000169414 SCV001371740 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.1548G>A (p.Trp516Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP's specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Therefore, PP4 and PM3_Strong can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). There is a ClinVar entry for this variant (Variation ID: 189025, 2 star review status) with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4.
Counsyl RCV000169414 SCV000220819 likely pathogenic Glycogen storage disease, type II 2014-10-20 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723388 SCV000224780 pathogenic not provided 2018-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000723388 SCV000890165 pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing The W516X variant has been reported in multiple unrelated patients with glycogen storage disease type II (GSDII) (Hermans et al. 2004; van et al. 2015; Elder et al. 2013; Bergsma et al. 2015; de Vries JM et al. 2010). The W516X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The W516X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.
Invitae RCV000169414 SCV000964272 pathogenic Glycogen storage disease, type II 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp516*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with low alpha-glucosidase enzyme activity, a finding that is highly specific for Pompe disease (PMID: 25243733, 22676651). This variant has been observed in many individuals affected with Pompe disease (PMID: 14695532, 29181627, 29122469, 24715333). ClinVar contains an entry for this variant (Variation ID: 189025). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000723388 SCV001245689 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169414 SCV001362499 pathogenic Glycogen storage disease, type II 2019-09-09 criteria provided, single submitter clinical testing Variant summary: GAA c.1548G>A (p.Trp516X) 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. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes. c.1548G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- eg Hermans_2004, deVries_2010, Messinger_2012, Stepien_2016). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Therapies Laboratory,Murdoch University RCV000169414 SCV001244229 pathogenic Glycogen storage disease, type II 2019-01-07 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000169414 SCV001422607 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp516Ter variant in GAA has been reported in at least 16 individuals (including at least 10 Caucasian individuals) with Glycogen Storage Disease II (PMID: 22676651, 25155446, 14695532, 17027861, 15048888, 18757064, 20826098, 22237443, 25243733, 24715333, 22252923, 26873529, 23601496), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189025). This variant has been identified in 0.002% (2/128904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140826989). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with 3 pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp516Ter variant is pathogenic (PMID: 20826098, 25243733, 22237443, 22676651; Variation ID: 4031, 4033). The phenotype of six individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity within fibroblasts or a dried blood spot (PMID: 20826098, 23601496, 22237443, 25243733, 26873529, 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2, PP4 (Richards 2015).

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