Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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 |
RCV000733496 | SCV000861573 | pathogenic | not provided | 2018-06-05 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
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). |
Ce |
RCV000733496 | SCV001747892 | pathogenic | not provided | 2021-10-01 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000733496 | SCV002025221 | likely pathogenic | not provided | 2019-09-19 | criteria provided, single submitter | clinical testing | |
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, |
RCV000410150 | SCV002092043 | pathogenic | Glycogen storage disease, type II | 2020-03-23 | no assertion criteria provided | clinical testing |