ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.399C>A (p.Tyr133Ter)

dbSNP: rs2039042313
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001200875 SCV001371776 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.399C>A (p.Tyr133Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and absence of gene product, meeting PVS1. When expressed in COS-1 cells, the variant results in no GAA activity and the mutant protein cannot be detected on Western blot, (PMID 14972326) supporting that it is a loss of function variant. The variant is absent in gnomAD v2.1.1, meeting PM2. A patient with infantile onset Pompe disease meeting the ClinGen LSD VCEP's specifications for PP4 has been reported who is homozygous for the variant; both parents were confirmed to be heterozygotes (PMID 14972326), meeting PM3_Supporting. There is no ClinVar entry for this varint. 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 LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

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