Submissions for variant NM_000152.5(GAA):c.471del (p.Thr158fs)

Minimum review status:		Collection method:
Minimum conflict level: Report conflict between different conditions
		ClinVar version:

Total submissions: 3

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000411817	SCV001443287	likely pathogenic	Glycogen storage disease, type II	2023-03-10	reviewed by expert panel	curation	The NM_000152.5:c.471del (p.Thr158ProfsTer8) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in patients with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 371501). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).
Counsyl	RCV000411817	SCV000487099	likely pathogenic	Glycogen storage disease, type II	2016-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000411817	SCV001579378	pathogenic	Glycogen storage disease, type II	2022-08-31	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr158Profs*8) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant has not been reported in the literature in individuals affected with GAA-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371501).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.