Submissions for variant NM_000152.5(GAA):c.852G>A (p.Ala284=)

gnomAD frequency: 0.00638  dbSNP: rs142626724

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000999779	SCV001371708	benign	Glycogen storage disease, type II	2020-01-23	reviewed by expert panel	curation	The highest continental population minor allele frequency for c.852G>A (p.Ala284=) in gnomAD v2.1.1 is 0.01017 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 188477, two star review status), with 5 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1.
PreventionGenetics, part of Exact Sciences	RCV000168659	SCV000302697	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000168659	SCV000518529	benign	not specified	2015-12-22	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.
Invitae	RCV000999779	SCV000626645	benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999779	SCV000883928	benign	Glycogen storage disease, type II	2021-10-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000999779	SCV001285458	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168659	SCV001363613	benign	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: GAA c.852G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.0063 in 248578 control chromosomes, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.852G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) without strong evidence of causality (Gort_2007, Herzog_2012, Kroos_2008) . These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000999779	SCV001754718	benign	Glycogen storage disease, type II	2021-07-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675221	SCV002545981	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GAA: BP4, BP7, BS1, BS2
Ambry Genetics	RCV002444675	SCV002678775	benign	Cardiovascular phenotype	2021-06-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675221	SCV000800866	benign	not provided	2016-12-30	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000675221	SCV001931987	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168659	SCV001974663	benign	not specified		no assertion criteria provided	clinical testing