Submissions for variant NM_000152.5(GAA):c.2481+16G>A

gnomAD frequency: 0.00252  dbSNP: rs41292408

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675247	SCV000110011	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000078173	SCV000519706	likely benign	not specified	2017-06-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249017	SCV001422874	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.2481+16G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by GeneDx and Mayo Clinic Genetic Testing Laboratories in ClinVar (Variation ID: 92478). This variant has been identified in 0.367% (413/112458) of European (non-Finnish) chromosomes, including 2 homozygotes, and 0.328% (106/32290) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs41292408). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249017	SCV001717000	benign	Glycogen storage disease, type II	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078173	SCV001748802	likely benign	not specified	2021-07-01	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2481+16G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 219566 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The frequency within the Non-Finnish European subpopulation is very close to the maximum frequency expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.0038 vs 0.0042), suggesting a possible benign role for the variant. To our knowledge, no occurrence of c.2481+16G>A in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign (n=1), likely benign (n=3), and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001249017	SCV002049378	benign	Glycogen storage disease, type II	2023-11-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000675247	SCV000800894	likely benign	not provided	2017-05-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000675247	SCV001797411	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000675247	SCV001930429	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000675247	SCV001968494	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925037	SCV004746638	likely benign	GAA-related disorder	2021-05-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).