Submissions for variant NM_000152.5(GAA):c.1552-13G>A

gnomAD frequency: 0.00276  dbSNP: rs111261964

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000392826	SCV004009591	likely benign	Glycogen storage disease, type II	2023-04-18	reviewed by expert panel	curation	The NM_000152.5:c.1552-13G>A variant is located near the acceptor splice region of intron 10 of GAA. The computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (BP4). To our knowledge, functional studies investigating the impact of this variant on splicing are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.004705 (607/129008 alleles) in the European non-Finnish population, which meets the ClinGen LSD VCEP’s threshold for BS1 (>0.005) when rounded up (BS1). There are 2 homozygotes in gnomAD v2.1.1. The variant was reported in a patient with Pompe disease along with a variant that has been classified as pathogenic by the ClinGen LD VCEP (c.841C>T (p.Arg281Trp); the phase was not reported in that patient (PMID: 31086307). However, analysis of clinical laboratory data in multiple patients with these two variants indicates that they likely occur in cis. There is a ClinVar entry for this variant (Variation ID: 255353). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): BS1, BP4. Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 18th, 2023).
PreventionGenetics, part of Exact Sciences	RCV000246280	SCV000302663	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000246280	SCV000338203	likely benign	not specified	2015-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000392826	SCV000407282	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	RCV000786312	SCV000724576	likely benign	not provided	2022-07-08	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000246280	SCV000917387	likely benign	not specified	2018-01-25	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.1552-13G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 788/277130 control chromosomes (2 homozygotes), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.004675 (592/126628)(gnomAD). This frequency is slightly above the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign and one other lab classified it as VUS. Taken together, this variant is classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000392826	SCV001423080	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.1552-13G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a likely benign variant (by GeneDx, EGL, and Prevention Genetics) and as a VUS (by Illumina) in ClinVar (Variation ID: 255353). This variant has been identified in 0.4705% (607/129008) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111261964). 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 (PMID: 25741868). 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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000392826	SCV001471012	likely benign	Glycogen storage disease, type II	2022-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV000392826	SCV001731733	benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786312	SCV002063662	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	GAA: BS2
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786312	SCV000925081	uncertain significance	not provided	2011-02-17	no assertion criteria provided	provider interpretation
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000786312	SCV001931932	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000246280	SCV001971118	benign	not specified		no assertion criteria provided	clinical testing