Submissions for variant NM_000152.5(GAA):c.726G>A (p.Ala242=)

gnomAD frequency: 0.00101  dbSNP: rs148578399

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000315968	SCV004227918	uncertain significance	Glycogen storage disease, type II	2023-09-19	reviewed by expert panel	curation	The NM_000152.5:c.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID: 36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID: 35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023)
Eurofins Ntd Llc (ga)	RCV000675220	SCV000338356	uncertain significance	not provided	2018-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315968	SCV000407269	uncertain significance	Glycogen storage disease, type II	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000675220	SCV000526123	likely benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing
Invitae	RCV000315968	SCV000626634	benign	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000315968	SCV001423083	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.726G>A (p.Ala242=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL and Illumina), a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories), and a benign variant (by Invitae) in ClinVar (Variation ID: 285366). This variant has been identified in 0.2769% (69/24916) of African chromosomes, including 1 homozygote, and 0.04516% (16/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148578399). 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 not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (Richards 2015).
Genome-Nilou Lab	RCV000315968	SCV001810418	likely benign	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000675220	SCV003834089	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165742	SCV003911694	uncertain significance	Cardiovascular phenotype	2023-01-06	criteria provided, single submitter	clinical testing	The c.726G>A variant (also known as p.A242A), located in coding exon 3 of the GAA gene, results from a G to A substitution at nucleotide position 726. This nucleotide substitution does not change the alanine at codon 242. This alteration has been reported in newborn screening programs for Pompe disease (Tang H et al. Int J Neonatal Screen, 2020 Mar;6:9; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6; Gragnaniello V et al. Mol Genet Metab Rep, 2022 Dec;33:100929; Burton BK et al. Int J Neonatal Screen, 2020 Mar;6:4). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000315968	SCV004565165	likely benign	Glycogen storage disease, type II	2023-09-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000675220	SCV000800865	likely benign	not provided	2015-12-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000315968	SCV002091959	likely benign	Glycogen storage disease, type II	2019-10-24	no assertion criteria provided	clinical testing