ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.276C>A (p.Cys92Ter)

dbSNP: rs1232001857
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000810454 SCV001371770 likely pathogenic Glycogen storage disease, type II 2024-10-29 reviewed by expert panel curation The NM_000152.5:c.276C>A (p.Cys92Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. and v4.1.0. (PM2_Supporting). To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 654482). The classification of this variant has been upgraded from Variant of Uncertain Significance to likely pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 29, 2024).
Labcorp Genetics (formerly Invitae), Labcorp RCV000810454 SCV000950653 pathogenic Glycogen storage disease, type II 2023-05-28 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 654482). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This sequence change creates a premature translational stop signal (p.Cys92*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000810454 SCV002810305 likely pathogenic Glycogen storage disease, type II 2024-03-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000810454 SCV004197847 likely pathogenic Glycogen storage disease, type II 2023-04-04 criteria provided, single submitter clinical testing

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