ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.246C>A (p.Cys82Ter)

dbSNP: rs749584846
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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 RCV002260939 SCV002540651 pathogenic Glycogen storage disease, type II 2022-01-04 reviewed by expert panel curation The NM_000152.5:c.246C>A (p.Cys82Ter) 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). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PMID: 33741225) (PP4_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PVS1, PM2_Supporting, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV002260939 SCV004375809 pathogenic Glycogen storage disease, type II 2023-03-18 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1693546). This premature translational stop signal has been observed in individual(s) with GAA-related conditions (PMID: 33741225). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys82*) 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).

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