ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.573C>A (p.Tyr191Ter) (rs376229714)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410905 SCV000485538 likely pathogenic Glycogen storage disease, type II 2016-01-04 criteria provided, single submitter clinical testing
Invitae RCV000410905 SCV001398596 pathogenic Glycogen storage disease, type II 2019-11-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr191*) 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 Pompe disease (PMID: 11738358, 30155607). ClinVar contains an entry for this variant (Variation ID: 370276). 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 RCV000410905 SCV001422882 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Tyr191Ter variant in GAA has been reported in 3 Spanish and 1 French individuals with Glycogen Storage Disease II (PMID: 11738358, 18505979, 25998610), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370276). This variant has been identified in 0.003% (1/34578) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376229714). 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 191, 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. This variant has been seen in combination with other variants curated in individuals with Glycogen Storage Disease II (PMID: 11738358, 18505979). The phenotype of individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity in patients consistent with disease (PMID: PMID: 18505979, 11738358). 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, PP4, PM2 (Richards 2015).

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