Submissions for variant NM_000152.5(GAA):c.258C>A (p.Pro86=)

gnomAD frequency: 0.00170  dbSNP: rs146615896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001001756	SCV004227905	likely benign	Glycogen storage disease, type II	2023-12-05	reviewed by expert panel	curation	The NM_000152.5: c.258C>A (p.Pro86=) variant in GAA is a synonymous variant with a highest population minor allele frequency in gnomAD v4.0.0 of 0.00509 (382/75054 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases (LD) VCEP’s threshold for BS1 (>0.005), meeting this criterion (BS1). The variant is not predicted to impact splicing; the nucleotide is not conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 282138). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4, BP7. (Classification approved by the ClinGen Lysosomal Diseases VCEP on December 5, 2023).
Eurofins Ntd Llc (ga)	RCV000338982	SCV000333379	benign	not specified	2015-07-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000590222	SCV000523296	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001001756	SCV000626585	benign	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590222	SCV000695657	likely benign	not provided	2017-02-03	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.258C>A (p.Pro86Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of an ESE site. These predictions have yet to be confirmed by functional studies. This variant was found in 69/114570 control chromosomes from ExAC, predominantly observed in the African subpopulation at a frequency of 0.006696 (64/9558). This frequency is about 1.6 times 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 African origin. No homozygotes have been reported in ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. A clinical diagnostic laboratory in ClinVar has classified this variant as benign. Taken together, this variant is classified as Likely Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001756	SCV001159368	benign	Glycogen storage disease, type II	2022-03-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590222	SCV004811206	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	GAA: BP4, BP7