Submissions for variant NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)

dbSNP: rs752921215

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000501120	SCV001371720	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP's PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all classifying the variant as 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_Very strong, PP4.
GeneDx	RCV000302789	SCV000329853	pathogenic	not provided	2016-06-08	criteria provided, single submitter	clinical testing	The W746X pathogenic variant in the GAA gene has been previously reported multiple times in association with both infantile-onset and late-onset GSDII (Beesley et al., 1998; Montalvo et al., 2006; Pittis et al., 2008). Clinical variability was described amongst individuals harboring the W746X variant and GAA enzyme activity ranged from decreased to absent (Montalvo et al., 2006; Remiche et al., 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W746X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Genetic Services Laboratory, University of Chicago	RCV000501120	SCV000594901	pathogenic	Glycogen storage disease, type II	2016-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000501120	SCV000752063	pathogenic	Glycogen storage disease, type II	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp746*) 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 (rs752921215, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 10206684, 24158270, 25488666). ClinVar contains an entry for this variant (Variation ID: 280063). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000302789	SCV000861727	pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501120	SCV000917394	pathogenic	Glycogen storage disease, type II	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2237G>A (p.Trp746X) 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 (eg. c.2560C>T, p.Arg854*). The variant allele was found at a frequency of 8.1e-06 in 245810 control chromosomes (gnomAD). c.2237G>A has been reported in the literature in multiple individuals affected with Late Onset Pompe Disease (Montalvo_2006, Liu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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	RCV000501120	SCV001422772	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp746Ter variant in GAA has been reported in at least 33 individuals (including 15 Italians, 5 from the UK, and 4 Chinese individuals) with Glycogen Storage Disease II (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254), and has also been reported pathogenic by GeneDx, UChicago, EGL Genetic Diagnostics, Integrated Genetics, and Invitae in ClinVar (Variation ID: 280063). This variant has been identified in 0.001% (1/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). 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 746, 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 the homozygous state and in trans with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 26497565, 16917947). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissues, consistent with disease (PMID: 26497565, 24158270, 22237443, 21484825, 17056254, 12923862, 18285536, 16917947). Another variant at the same position with the same amino acid change, c.2238G>A (p.Trp746Ter), has been reported as a pathogenic and likely pathogenic variant in association with Glycogen Storage Disease II in ClinVar (Variation ID: 370904). 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_VeryStrong, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000302789	SCV002021188	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000501120	SCV002789737	pathogenic	Glycogen storage disease, type II	2021-12-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000501120	SCV004195420	pathogenic	Glycogen storage disease, type II	2024-02-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000501120	SCV002092116	pathogenic	Glycogen storage disease, type II	2020-08-31	no assertion criteria provided	clinical testing