Submissions for variant NM_000152.5(GAA):c.1478C>T (p.Pro493Leu)

gnomAD frequency: 0.00004  dbSNP: rs148842275

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000666526	SCV001371749	likely pathogenic	Glycogen storage disease, type II	2024-07-21	reviewed by expert panel	curation	The NM_000152.5:c.1478C>T variant in GAA is predicted to result in the substitution of proline by leucine at amino acid 493 (p.Pro493Leu). At least 7 probands have been reported with this variant, including one adult and an affected sibling with documented values showing GAA activity below the normal range on dried blood spot assay, and treated with enzyme replacement therapy (ERT) (PMID 24495340), and another four individuals with features consistent with Pompe disease, three of them on enzyme replacement therapy (PMID: 25455803, 29181627, 31545528, 33188503). Furthermore, three individuals with the same genotype (thought to be unrelated but cannot be confirmed) were identified in a clinical diagnostic laboratory with GAA activity below the normal range on dried blood spot (PP4_Moderate). Two additional patients have been reported with P493L, but the cDNA change was not provided and, one patient was heterozygous without the identification of a second variant, therefore, this data will not be included (PMID: 20033296, 23160972, 31545528), and patient with suspected late onset Pompe disease was identified by newborn screening but was asymptomatic (PMID: 33202836). The 7 probands are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all of these patients. The second variant is either c.525delT (PMID: 25455803, and 3 presumably unrelated patients identified by a clinical diagnostic laboratory, max 2 patients counted, ClinVar Variation ID: 4033, SCV001443331.1; 2 x 0.5 points), c.1134C>G (p.Tyr378Ter), phase unknown (PMID: 29181627, ClinVar Variation ID: 595469, SCV001443283.2, 0.5 points), c.307T>G (p.Cys103Gly) (PMID: 24495340, ClinVar Variation ID: 92483, SCV002817442.1, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1, 0.5 points), c.1655T>C (p.Leu552Pro) (PMID: 31545528, ClinVar Variation ID: 279811, SCV001371750.2) or c.-32-13T>G (PMID: 33188503, ClinVar Variation ID: 4027). 7 x 0.5 points = 3.5 points (PM3_Strong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003 (4/128962 alleles) in the European non-Finnish population, and in gnomAD v4.1. the MAF is 0.00001695 (20/1180038) in the European non-Finnish population. Both are 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 0.911 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, results of functional studies are not available for this variant. There is a ClinVar entry for this variant (Variation ID 379593). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 21, 2024)
GeneDx	RCV000443985	SCV000516792	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24495340, 25455803, 20033296, 33202836, 27896092, 33188503, 29181627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666526	SCV000946429	pathogenic	Glycogen storage disease, type II	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 493 of the GAA protein (p.Pro493Leu). This variant is present in population databases (rs148842275, gnomAD 0.003%). This missense change has been observed in individual(s) with reduced α-glucosidase acitivity (PMID: 20033296, 24495340, 25455803, 29181627). ClinVar contains an entry for this variant (Variation ID: 379593). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV000666526	SCV001422627	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Pro493Leu variant in GAA has been reported in 6 individuals from Germany or Austria with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 29181627, 24495340, 23160972, 20033296, 25455803), and has also been reported likely pathogenic by GeneDx and Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 379593). This variant has been identified in 0.003% (4/128962) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148842275). 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 combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Pro493Leu variant is pathogenic (PMID: 20033296, 24495340). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in dried blood spots, consistent with disease (PMID: 20033296, 24495340). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4, PM3_Supporting (Richards 2015).
Revvity Omics, Revvity	RCV000443985	SCV002025191	likely pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000666526	SCV002060169	likely pathogenic	Glycogen storage disease, type II	2021-11-08	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1478C>T(P493L) is a missense variant classified as likely pathogenic in the context of Pompe disease. P493L has been observed in cases with relevant disease (PMID: 25455803, 5614309, 29181627, 29653542). Functional assessments of this variant are not available in the literature. P493L has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, NM_000152.3(GAA):c.1478C>T(P493L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000666526	SCV002813255	likely pathogenic	Glycogen storage disease, type II	2024-05-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666526	SCV004195494	pathogenic	Glycogen storage disease, type II	2023-12-27	criteria provided, single submitter	clinical testing