ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1961C>A (p.Ser654Ter)

dbSNP: rs1057518106
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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 RCV001200860 SCV001371714 likely pathogenic Glycogen storage disease, type II 2023-03-10 reviewed by expert panel curation The NM_000152.5:c.1961C>A (p.Ser654Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individual with Pompe disease. However, there is a ClinVar entry for this variant (Variation ID 372968). 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 met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).
GeneDx RCV000414717 SCV000491511 likely pathogenic not provided 2016-06-16 criteria provided, single submitter clinical testing The S654X variant in the GAA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S654X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S654X is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

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