ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1134C>G (p.Tyr378Ter)

dbSNP: rs1567830317
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001265218 SCV001443283 pathogenic Glycogen storage disease, type II 2023-07-03 reviewed by expert panel curation The NM_000152.5:c.1134C>G (p.Tyr378Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 7/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients with this variant have been reported with Pompe disease, both treated with enzyme replacement therapy (PMID: 29181627, 31392188) (PP4). One of these individuals is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (PMID: 31392188). The second patient is compound heterozygous for the variant and c.1478C>T (p.Pro493Leu) (PMID: 29181627); the allelic data for this patient will be used in the classification of p.Pro493Leu and was not included here to avoid circular logic (PM3_Supporting). This variant was absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 595469). 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 Lysosomal Diseases VCEP: PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023)
Eurofins Ntd Llc (ga) RCV000731020 SCV000858790 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing

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