Submissions for variant NM_000152.5(GAA):c.324T>C (p.Cys108=)

gnomAD frequency: 0.71989  dbSNP: rs1800300

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000284275	SCV001371707	benign	Glycogen storage disease, type II	2020-01-21	reviewed by expert panel	curation	The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian 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: 92484, two star review status), with 10 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.
Eurofins Ntd Llc (ga)	RCV000078180	SCV000110018	benign	not specified	2018-09-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078180	SCV000151260	benign	not specified	2013-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078180	SCV000302686	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000284275	SCV000407257	benign	Glycogen storage disease, type II	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000299885	SCV000483696	benign	Primary ciliary dyskinesia	2016-06-14	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000284275	SCV000679832	benign	Glycogen storage disease, type II	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587169	SCV000695661	benign	not provided	2017-05-03	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 86202/117014 control chromosomes (32095 homozygotes) at a frequency of 0.7366811, indicating the C allele is the major allele. This frequency is approximately 175 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant has been classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000078180	SCV000711747	benign	not specified	2017-05-08	criteria provided, single submitter	clinical testing	p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 82% (13463/16390) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1800300).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000284275	SCV001730023	benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000284275	SCV001738007	benign	Glycogen storage disease, type II	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000587169	SCV001937502	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321569	SCV002609864	benign	Cardiovascular phenotype	2015-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000587169	SCV005248712	benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000284275	SCV000733721	benign	Glycogen storage disease, type II		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587169	SCV000800857	benign	not provided	2015-10-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000284275	SCV001453582	benign	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587169	SCV001553818	uncertain significance	not provided		no assertion criteria provided	clinical testing	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 82.142% in ExAC) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078180	SCV001926273	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078180	SCV001954062	benign	not specified		no assertion criteria provided	clinical testing