Submissions for variant NM_000152.5(GAA):c.1832G>A (p.Gly611Asp)

dbSNP: rs1057517105

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000409030	SCV002583370	likely pathogenic	Glycogen storage disease, type II	2022-09-06	reviewed by expert panel	curation	The NM_000152.5:c.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID: 22252923) or in the affected range in dried blood spot assay (PMID: 25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID: 24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID: 24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID: 25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. 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 Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.
Counsyl	RCV000409030	SCV000486756	likely pathogenic	Glycogen storage disease, type II	2016-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409030	SCV000963791	pathogenic	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 611 of the GAA protein (p.Gly611Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease and reduced GAA enzymatic activity (PMID: 22252923, 24269976, 25681614; Invitae). ClinVar contains an entry for this variant (Variation ID: 371226). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409030	SCV001422658	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly611Asp variant in GAA has been reported in 4 individuals (including 1 Chinese individual) with Glycogen Storage Disease II (PMID: 25681614, 22252923, 24269976), and has also been reported as a likely pathogenic variant by Counsyl and Invitae in ClinVar (Variation ID: 371226). This variant was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Gly611Asp variant is pathogenic (PMID: 25681614). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA enzyme in a dried blood spot, consistent with disease (PMID: 25681614). In summary, the clinical significance of the p.Gly611Asp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015).
Baylor Genetics	RCV000409030	SCV004197872	likely pathogenic	Glycogen storage disease, type II	2023-01-25	criteria provided, single submitter	clinical testing