Submissions for variant NM_000152.5(GAA):c.533G>A (p.Arg178His)

gnomAD frequency: 0.00008  dbSNP: rs762267535

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670700	SCV000795590	uncertain significance	Glycogen storage disease, type II	2017-11-09	criteria provided, single submitter	clinical testing
Invitae	RCV000670700	SCV000954448	pathogenic	Glycogen storage disease, type II	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the GAA protein (p.Arg178His). This variant is present in population databases (rs762267535, gnomAD 0.004%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21232767, 29143201, 33202836). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554969). 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%. Studies have shown that this missense change does not affect mRNA splicing (PMID: 31301153). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000670700	SCV001423032	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Arg178His variant in GAA has been reported in one Taiwanese individual with glycogen storage disease II (PMID: 21232767), and has been identified in 0.004% (1/23728) of African chromosomes and 0.003% (4/122358) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762267535). 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 (VariationID: 554969). In vitro functional studies using COS-1 and fibroblast cells provide some evidence that the p.Arg178His variant may slightly impact protein function (PMID: 23632029). 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. 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, PS3_Supporting (Richards 2015).
Genome-Nilou Lab	RCV000670700	SCV002027220	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805792	SCV002051399	uncertain significance	not specified	2021-12-28	criteria provided, single submitter	clinical testing	Variant summary: GAA c.533G>A (p.Arg178His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 238840 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.533G>A has been reported in the literature as a VUS in compound heterozygous genotype with a reportedly Asian pseudodeficiency allele (example, Chien_2011) or as a homozygous genotype in another newborn with an unknown phenotype (example, Burlina_2017) for Glycogen Storage Disease, Type 2 (Pompe Disease). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). A mutational update as of 2021 lists this variant among the VUS found through NBS programs (de Farla_2021). At least one publication reports experimental evidence evaluating an impact on protein function in vitro (Chien_2013). The most pronounced variant effect results in approximately 10%-<30% of normal activity of the mutant form transfected into COS-1 cells measured using 4-MU as a substrate. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV003129985	SCV003810577	uncertain significance	not provided	2023-12-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670700	SCV004195454	pathogenic	Glycogen storage disease, type II	2023-10-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003129985	SCV004224234	likely pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3
Natera, Inc.	RCV000670700	SCV002091927	uncertain significance	Glycogen storage disease, type II	2020-02-19	no assertion criteria provided	clinical testing