ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.343C>T (p.Gln115Ter)

dbSNP: rs786204614
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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 RCV000169376 SCV001443281 pathogenic Glycogen storage disease, type II 2023-03-07 reviewed by expert panel curation The NM_000152.5(GAA):c.343C>T (p.Gln115Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least three individuals have been reported to have Pompe disease and this variant (PMIDs 17041744, 17616415, 32528171). GAA activity is reduced in the patients for whom it was reported (13-35% normal) but PP4 was not applied because the activity does not meet the strict thresholds specified by the ClinGen LD VCEP. ONe of these individuals is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1076-1G>C, phase unknown (PMID: 17616415). Two additional reports describe a child who is compound heterozygous for the variant and p.Pro482Leu (PMID: 17041744, 17616415). The allelic data will be used in the classification of p.Pro482Leu and is not included here to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 188996). 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 LD VCEP (specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting.
Counsyl RCV000169376 SCV000220760 likely pathogenic Glycogen storage disease, type II 2014-10-01 criteria provided, single submitter literature only
Broad Institute Rare Disease Group, Broad Institute RCV000169376 SCV003761379 pathogenic Glycogen storage disease, type II 2023-01-25 criteria provided, single submitter curation The heterozygous p.Gln115Ter variant in GAA was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 4027), in one individual with myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 4027), however the phase of these variants is unknown at this time. The p.Gln115Ter variant in GAA has been previously reported in at least two unrelated individuals with glycogen storage disease II (PMID: 17616415, PMID: 17041744). These two affected individuals were compound heterozygotes who carried pathogenic or likely pathogenic in trans (PMID: 17616415, PMID: 17041744, ClinVar Variation ID: 982297, 1353052), which increases the likelihood that the p.Gln115Ter variant in GAA is pathogenic. This variant has also been reported in ClinVar (Variation ID: 188996) and has been interpreted as likely pathogenic by Counsyl and the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 115, 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. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015).

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