ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1564C>G (p.Pro522Ala)

dbSNP: rs892129065
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000410150 SCV004809077 pathogenic Glycogen storage disease, type II 2024-03-19 reviewed by expert panel curation The NM_000152.5:c.1564C>G variant in GAA is a missense variant predicted to cause substitution of proline by alanine at amino acid 522 (p.Pro522Ala). This variant has been detected in at least 7 unrelated patients reported to have Pompe disease including four individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 26800218, 33301762, 34072668, Duke University), and three for whom GAA activity was not reported (PMID: 18429042, 37087815) (PP4_Moderate). Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP: c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 18429042), c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728, SCV001371736.1) (PMID: 18429042), c.1465G>A (p.Asp489Asn) (ClinVar Variation ID: 92465, SCV003852732.1) (PMID: 34072668), and c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 26800218, 37087815, Clinical Diagnostic Laboratory; at least 3 unrelated patients). The phase is not confirmed for any of these individuals. One individual was homozygous for this variant (PMID: 33301762) (PM3_Strong). Another missense variant, c.1564C>T, p.Pro522Ser (ClinVar Variation ID: 972746) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cell line resulted in 0% wild type GAA activity when measured using fluorogenic substrate 4-methylumbelliferyl-α-D glucopyranoside. This was further supported via Western blot analysis demonstrating deficient GAA protein expression (PMID: 18429042) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883 which is above the threshold predicting a damaging (>0.7) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 371277). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PM5_Supporting PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).
Counsyl RCV000410150 SCV000486817 likely pathogenic Glycogen storage disease, type II 2016-08-12 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000733496 SCV000861573 pathogenic not provided 2018-06-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410150 SCV001582302 pathogenic Glycogen storage disease, type II 2023-07-25 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 371277). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 18429042). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This missense change has been observed in individual(s) with Pompe disease (PMID: 17643989, 18429042, 26800218, 29422078). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 522 of the GAA protein (p.Pro522Ala).
CeGaT Center for Human Genetics Tuebingen RCV000733496 SCV001747892 pathogenic not provided 2021-10-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000733496 SCV002025221 likely pathogenic not provided 2019-09-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000410150 SCV002813919 pathogenic Glycogen storage disease, type II 2022-02-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000410150 SCV004197887 pathogenic Glycogen storage disease, type II 2022-10-31 criteria provided, single submitter clinical testing
Natera, Inc. RCV000410150 SCV002092043 pathogenic Glycogen storage disease, type II 2020-03-23 no assertion criteria provided clinical testing

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