Submissions for variant NM_000152.5(GAA):c.1402A>T (p.Ile468Phe)

gnomAD frequency: 0.00001  dbSNP: rs886043148

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000673833	SCV004227915	likely pathogenic	Glycogen storage disease, type II	2023-12-19	reviewed by expert panel	curation	The NM_000152.5:c.1402A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 468 (p.Ile468Phe). This variant has been identified in at least four unrelated individuals described as having Pompe disease, including two patients with LOPD receiving ERT (PMID: 37701327, 25037089). One of these patients has documented deficiency of GAA in DBS. One individual is part of a cohort of patients with LOPD receiving ERT, although GAA enzyme is not reported (PMID: 37701327). This meets criteria for PP4_moderate. This variant has been reported in compound heterozygosity (phase unknown) in three unrelated patients with the common splice site variant c.-32-13T>G, meeting criteria for PM3. It has also been reported in one individual with confirmed deficient GAA in DBS, muscle, and skin fibroblast with no second variant reported on sequencing or deletion/duplication analysis (PMID: 25037089). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002 (1/59986 alleles) in the Admixed American population, which is 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 0.747, which meets the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 269826), 1-star review status) with 9 submitters classifying the variant as likely pathogenic (1) and uncertain significance (8). 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 Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023).
Eurofins Ntd Llc (ga)	RCV000386415	SCV000338675	uncertain significance	not provided	2016-01-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000673833	SCV000799080	uncertain significance	Glycogen storage disease, type II	2018-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673833	SCV001206269	likely pathogenic	Glycogen storage disease, type II	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 468 of the GAA protein (p.Ile468Phe). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Pompe disease (PMID: 25037089, 30564623, 31086307, 31342611). ClinVar contains an entry for this variant (Variation ID: 285589). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000673833	SCV001422693	uncertain significance	Glycogen storage disease, type II	2020-01-15	criteria provided, single submitter	curation	The p.Ile468Phe variant in GAA has been reported in two individuals with glycogen storage disease II (PMID: 25037089) and has been identified in 0.013% (2/15414) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043148). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Counsyl and EGL Genetic Diagnostics (VariationID: 285589). 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 phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 25037089). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 25037089) and in an individual with glycogen storage disease II increases the likelihood that the p.Ile468Phe variant is pathogenic. 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, PM3_supporting, PP4 (Richards 2015).
GeneDx	RCV000386415	SCV001986139	uncertain significance	not provided	2019-12-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25037089, 30564623, 31086307)
Genome-Nilou Lab	RCV000673833	SCV002027271	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000673833	SCV002776955	uncertain significance	Glycogen storage disease, type II	2021-07-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000386415	SCV003816184	likely pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000673833	SCV004197878	likely pathogenic	Glycogen storage disease, type II	2022-12-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000673833	SCV001455614	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing