ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2214G>A (p.Trp738Ter) (rs1057516328)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409827 SCV000485477 likely pathogenic Glycogen storage disease, type II 2015-12-15 criteria provided, single submitter clinical testing
Invitae RCV000409827 SCV001211539 pathogenic Glycogen storage disease, type II 2019-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp738*) 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 individual(s) with glycogen storage disease (PMID: 22676651). ClinVar contains an entry for this variant (Variation ID: 370223). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000409827 SCV001422610 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp738Ter variant in GAA has been reported in 2 Chinese and 2 German individuals with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 21644219, 22676651), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370223). This variant has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516328). 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 738, 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 a pathogenic variant, and in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Trp738Ter variant is pathogenic (PMID: 22676651). The phenotype of an individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity less than 10% of WT, consistent with disease (PMID: 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 low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4, PM2 (Richards 2015).

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