Submissions for variant NM_000152.5(GAA):c.1735G>A (p.Glu579Lys)

gnomAD frequency: 0.00002  dbSNP: rs991082382

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000586125	SCV002817434	pathogenic	Glycogen storage disease, type II	2022-12-06	reviewed by expert panel	curation	The NM_000152.:c.1735G>A variant in GAA is a missense variant predicted to result in the substitution of glutamate by lysine at amino acid 579 (p.Glu579Lys). Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID: 21676566, 23601496, 29124014, 34357340), one with reported features consistent with infantile-onset Pompe disease (PMID: 24269976), and another reported to have Pompe disease (PMID: 14695532) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID: 34357340) (0.5 points), c.525delT (PMID: 14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID: 24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMIDs: 23601496, 31086307,31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID: 14695532, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.878 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 495664). In summary this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the Clingen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 6, 2022)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586125	SCV000695643	pathogenic	Glycogen storage disease, type II	2016-09-22	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.1735G>A (p.Glu579Lys) variant located in the glycoside hydrolase superfamily domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/5 in silico tools predicting a "damaging" outcome, which is supported by multiple functional studies. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and multiple publications cite the variant in compound heterozygote affected individuals. Therefore, the variant of interest has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000586125	SCV001423068	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Glu579Lys variant in GAA has been reported in 4 individuals (including 1 Australian, 1 Japanese, 1 Chinese, and 1 Caucasian individuals) with Glycogen Storage Disease II (PMID: 21676566, 14695532, 24269976, 23601496), and has also been reported pathogenic by Integrated Genetics in ClinVar (Variation ID: 495664). This variant has been identified in 0.002% (2/129092) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs991082382). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Glu579Lys variant may impact GAA processing and activity (PMID: 14695532). However, these types of assays may not accurately represent biological function. 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 combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Glu579Lys variant is pathogenic (PMID: 23601496). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in their skin fibroblasts or muscle (PMID: 23601496, 21676566). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PS3, PM2, PP3, PP4 (Richards 2015).
Invitae	RCV000586125	SCV001582303	pathogenic	Glycogen storage disease, type II	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 579 of the GAA protein (p.Glu579Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with Pompe disease (PMID: 14695532, 21676566, 24269976, 29124014, 31342611). ClinVar contains an entry for this variant (Variation ID: 495664). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001783090	SCV002025190	likely pathogenic	not provided	2020-11-29	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001783090	SCV002503218	likely pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000586125	SCV002781464	pathogenic	Glycogen storage disease, type II	2022-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000586125	SCV004197819	pathogenic	Glycogen storage disease, type II	2023-06-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000586125	SCV001132195	likely pathogenic	Glycogen storage disease, type II	2018-12-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000586125	SCV002092056	pathogenic	Glycogen storage disease, type II	2020-09-24	no assertion criteria provided	clinical testing