ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1496G>A (p.Trp499Ter) (rs766680292)

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Total submissions: 3
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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 RCV000673032 SCV001443321 pathogenic Glycogen storage disease, type II 2020-10-05 reviewed by expert panel curation This variant, c.1496G>A (p.Trp499Ter) is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross reactive immunological material in cultured skin fibroblasts from a patient with this variant (PMIDs 19775921, 22252923, and 25741864). Therefore, PVS1 can be applied. This patient, who has infantile onset Pompe disease, meets the ClinGen LSD VCEP's specifications for PP4, and is homozygous for the variant, meeting PM3_Supporting. Additional patients have been reported, including 2 homozygous Tunisian patients (PMID 32125626), but the residual GAA activity was not provided, and this data was not included. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which meets PM2. There is a ClinVar entry for this variant (Variation ID 556959, 1 star review status), with one submitter 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. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Counsyl RCV000673032 SCV000798197 likely pathogenic Glycogen storage disease, type II 2018-03-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000673032 SCV001422697 pathogenic Glycogen storage disease, type II 2020-01-23 no assertion criteria provided curation The p.Trp499Ter variant in GAA has been reported in at least 3 individuals with glycogen storage disease (PMID: 19775921, 18425781, 22252923) and has been identified in 0.003% (1/34586) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766680292). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as likely pathogenic by Counsyl (Variation ID: 556959). This nonsense variant leads to a premature termination codon at position 499, 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. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 19775921). Additionally, the homozygous occurrence of this variant and in an individual with glycogen storage disease (PMID: 19775921) slightly increases the likelihood that the p.Trp499Ter variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for GAA in an autosomal recessive manner based on the prediction that it causes loss of function of the GAA gene, its low frequency in the general population, and the homozygous occurrence of the variant in an affected individual. ACMG/AMP Criteria applied: PVS1, PM2, PP4, PM3_supporting (Richards 2015).

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