ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)

dbSNP: rs755253527
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001078141 SCV004227902 likely pathogenic Glycogen storage disease, type II 2023-11-21 reviewed by expert panel curation The NM_000152.5:c.1082C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 361 (p.Pro361Arg). This variant has been observed in the literature in two cases consistent with late-onset Pompe disease (PMID: 30312517, 32012848) with documented GAA deficiency. Both met PP4 specifications (PP4_Moderate), in compound heterozygosity with the known pathogenic variant c.-32-13T>G, phase not confirmed (PM3). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000008993 (1/1111956 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.945 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.1082C>T, p.Pro361Leu) (ClinVar Variation ID: 403712) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 289367, 1-star review status) with 2 submitter, classifying this variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PM3, PM2_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023).
Eurofins Ntd Llc (ga) RCV000382384 SCV000343716 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing
Molecular Therapies Laboratory, Murdoch University RCV001078141 SCV001156139 pathogenic Glycogen storage disease, type II no assertion criteria provided clinical testing Elevated CK (950 units); low GAA enzyme activity (0.8 units); urine tetrasaccharides elevated (40 units); respiratory functions normal

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