Submissions for variant NM_000152.5(GAA):c.1130del (p.Gly377fs)

dbSNP: rs754134578

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249090	SCV001443328	likely pathogenic	Glycogen storage disease, type II	2023-05-26	reviewed by expert panel	curation	The NM_000152.5:c.1130del (p.Gly377AlafsTer15) variant in GAA is a frameshift variant that is 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). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002354 (3/127432 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting) To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 497032). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. 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 ).GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications version 2.0): PVS1, PM2_Supporting.
Eurofins Ntd Llc (ga)	RCV000596780	SCV000701128	pathogenic	not provided	2017-04-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249090	SCV001423062	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly377AlafsTer15 variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II and has been identified in 0.0023% (3/127432) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant has been reported pathogenic by EGL in ClinVar (Variation ID: 497032). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 377 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).