Submissions for variant NM_000152.5(GAA):c.1548G>A (p.Trp516Ter)

gnomAD frequency: 0.00004  dbSNP: rs140826989

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169414	SCV001371740	pathogenic	Glycogen storage disease, type II	2020-02-14	reviewed by expert panel	curation	This variant, c.1548G>A (p.Trp516Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP's specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Therefore, PP4 and PM3_Strong can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). There is a ClinVar entry for this variant (Variation ID: 189025, 2 star review status) with 5 submitters 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4.
Counsyl	RCV000169414	SCV000220819	likely pathogenic	Glycogen storage disease, type II	2014-10-20	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000723388	SCV000224780	pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000723388	SCV000890165	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Reported in multiple unrelated patients with glycogen storage disease type II (GSDII) (Hermans et al. 2004; van et al. 2015; Elder et al. 2013; Bergsma et al. 2015; de Vries JM et al. 2010); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22252923, 18757064, 34134972, 31965297, 32888769, 31086307, 25525159, 25155446, 29181627, 25541616, 22676651, 24715333, 20826098, 23601496, 15048888, 25243733, 14695532)
Invitae	RCV000169414	SCV000964272	pathogenic	Glycogen storage disease, type II	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp516*) 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 is present in population databases (rs140826989, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Pompe disease and low alpha-glucosidase enzyme activity (PMID: 14695532, 22676651, 24715333, 25243733, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 189025). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000723388	SCV001245689	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169414	SCV001362499	pathogenic	Glycogen storage disease, type II	2019-09-09	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1548G>A (p.Trp516X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes. c.1548G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- eg Hermans_2004, deVries_2010, Messinger_2012, Stepien_2016). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169414	SCV001422607	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp516Ter variant in GAA has been reported in at least 16 individuals (including at least 10 Caucasian individuals) with Glycogen Storage Disease II (PMID: 22676651, 25155446, 14695532, 17027861, 15048888, 18757064, 20826098, 22237443, 25243733, 24715333, 22252923, 26873529, 23601496), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189025). This variant has been identified in 0.002% (2/128904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140826989). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 516, which is 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. The presence of this variant in combination with 3 pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp516Ter variant is pathogenic (PMID: 20826098, 25243733, 22237443, 22676651; Variation ID: 4031, 4033). The phenotype of six individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity within fibroblasts or a dried blood spot (PMID: 20826098, 23601496, 22237443, 25243733, 26873529, 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000723388	SCV002021166	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing
DASA	RCV000169414	SCV002061203	pathogenic	Glycogen storage disease, type II	2022-01-05	criteria provided, single submitter	clinical testing	The c.1548G>A;p.(Trp516*) variant creates a premature translational stop signal in the GAA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 189025; PMID: 32317649; 30155607; 29181627; 29122469; 26873529) - PS4. The variant is present at low allele frequencies population databases (rs140826989 – gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp516*) was detected in trans with a pathogenic variant (PMID: 32317649; 29181627; 29122469; 26873529) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000723388	SCV002502328	pathogenic	not provided	2021-09-08	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000169414	SCV002580255	pathogenic	Glycogen storage disease, type II	2021-09-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169414	SCV002803720	pathogenic	Glycogen storage disease, type II	2021-10-16	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000169414	SCV004046207	pathogenic	Glycogen storage disease, type II		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 10 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with Glycogen storage disease II (PMID: 14695532, 29181627, 29122469, 24715333). Loss-of-function variation in GAA is an established mechanism of disease (PMID:18425781, 22252923). This variant has been observed in individuals with low alpha-glucosidase enzyme activity, suggestive of Glycogen storage disease II (PMID: 25243733, 22676651).The c.1548G>A (p.Trp516Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00007 (2/282510) and thus is presumed to be rare. Based on the available evidence, the c.1548G>A (p.Trp516Ter) variant is classified as a Pathogenic.
Baylor Genetics	RCV000169414	SCV004197812	pathogenic	Glycogen storage disease, type II	2023-06-22	criteria provided, single submitter	clinical testing
Molecular Therapies Laboratory, Murdoch University	RCV000169414	SCV001244229	pathogenic	Glycogen storage disease, type II	2019-01-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169414	SCV001455619	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723388	SCV001930424	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723388	SCV001968560	pathogenic	not provided		no assertion criteria provided	clinical testing