Submissions for variant NM_000152.5(GAA):c.2544del (p.Lys849fs)

dbSNP: rs398123173

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249089	SCV002032118	pathogenic	Glycogen storage disease, type II	2021-12-02	reviewed by expert panel	curation	The NM_000152.5: c.2544del (p.Lys849ArgfsTer38) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20. Although the premature stop codon is thought to occur in the penultimate exon of the gene, it is not within the last 50 base pairs of the exon and, therefore, it is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. A patient with this variant has been reported to have no GAA cross-reactive material (CRIM-negative)(PMID 23763753), supporting that this variant is a loss of function variant (PVS1). This patient, who has symptoms consistent with infantile onset Pompe disease, and another individual with late-onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID 30363678), both meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. The first patient (CRIM-negative) is compound heterozygous for the variant and a "complex deletion". Because details of the complex deletion are unavailable, this data was not included for PM3. The second patient is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 30363678)(0.5 points, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 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). There is a ClinVar entry for this variant (Variation ID: 92480, one star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.
Eurofins Ntd Llc (ga)	RCV000175264	SCV000226721	pathogenic	not provided	2015-12-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249089	SCV001423059	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Lys849ArgfsTer38 variant in GAA has been reported in 1 individual with Glycogen Storage Disease II (DOI: 10.1186/1471-2474-14-S2-P3), and has also been reported pathogenic by EGL in ClinVar (Variation ID: 92480). This variant has been identified in 0.0009% (1/112244) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123173). 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 849 and leads to a premature termination codon 38 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. This variant was seen in combination with a complex deletion and in an individual with Glycogen Storage Disease II (DOI: 10.1186/1471-2474-14-S2-P3). 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).
Baylor Genetics	RCV001249089	SCV004195475	pathogenic	Glycogen storage disease, type II	2023-09-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017389	SCV004847981	pathogenic	Glycogen storage disease	2015-12-23	criteria provided, single submitter	clinical testing	The p.Lys849fs variant in GAA has been reported in 1 Caucasian individual with glycogen storage disease II, who was compound heterozygous with a second pathogenic GAA variant. The variant has been identified in 1/65646 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs398123173). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 849 and leads to a premature termination codon 38 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, the p.Lys849fs variant is pathogenic.