Submissions for variant NM_000152.5(GAA):c.1310G>A (p.Arg437His)

gnomAD frequency: 0.00023  dbSNP: rs150868652

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000553754	SCV000626504	uncertain significance	Glycogen storage disease, type II	2022-10-17	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 437 of the GAA protein (p.Arg437His). This variant is present in population databases (rs150868652, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456374). 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 not expected to disrupt GAA protein function. This variant disrupts the p.Arg437 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12601120, 17805474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000553754	SCV001281357	uncertain significance	Glycogen storage disease, type II	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000553754	SCV001422735	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Arg437His variant in GAA has been reported in one individual with suspected glycogen storage disease II (PMID: 25681614) and has been identified in 0.041% (9/21742) of African chromosomes, 0.007% (8/109392) of European (non-Finnish) chromosomes, and 0.007% (2/27668) of South Asian chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150868652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier disease. This variant has also been reported in ClinVar as a VUS by Invitae (VariationID: 456374). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg437Cys, has been reported pathogenic in association with glycogen storage disease II in the literature and ClinVar (PMID: 19862843, 24190153, 21984055, 21704464, 12601120, 24169249, 22521436, 17805474, 25388776, 25526786, 23884227, 18495398; VariationID: 189082). In summary, the clinical significance of the p.Arg437His variant is uncertain. ACMG/AMP Criteria applied: PM5, PM2, BP4 (Richards 2015).
Genome-Nilou Lab	RCV000553754	SCV002027263	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000553754	SCV002792987	uncertain significance	Glycogen storage disease, type II	2022-02-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000553754	SCV004565266	uncertain significance	Glycogen storage disease, type II	2023-03-09	criteria provided, single submitter	clinical testing	The GAA c.1310G>A; p.Arg437His variant (rs150868652), is reported in the literature in one individual suspected of Pompe disease (Turaca 2015). This variant is also reported in ClinVar (Variation ID: 456374), and is found in the general population with an overall allele frequency of 0.008% (20/246812 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1309C>T, p.Arg437Cys) have been reported in individuals with Pompe disease and are considered pathogenic (Fukuhara 2017, Park 2021). Computational analyses predict that this variant is neutral (REVEL: 0.289). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Turaca LT et al. Novel GAA mutations in patients with Pompe disease. Gene. 2015 Apr 25;561(1):124-31. PMID: 25681614. Park KS. Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population. Children (Basel). 2021 Jul 16;8(7):601. PMID: 34356580. Fukuhara Y et al. A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. Mol Genet Metab Rep. 2017 Oct 31;14:3-9. PMID: 29124014.
Natera, Inc.	RCV000553754	SCV001455609	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing