Submissions for variant NM_000152.5(GAA):c.2238G>A (p.Trp746Ter)

dbSNP: rs1800312

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000410158	SCV001371729	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	This variant, c.2238G>A (p.Trp746Ter), is a nonsense variant, predicted to result in nonsense mediated decay and lack 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 cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923), as well as functional studies in which there was no measurable GAA activity when the variant was expressed in HEK-293 cells (PMID 23430493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, meeting PM2. This variant has been reported in 3 patients who meet the ClinGen LSD VCEP's specifications for PP4. Two of these patients are compound heterozygous for pathogenic variants, either c.-32-13T>G or c.1826dupA (PMIDs 16860134, 22613277, 25741864). The phase is unknown. This data meets PM3. Another patient is compound heterozygous for the variant and c.1843G>A (p.Gly615Arg). This in trans data was used in the assessment of p.Gly615Arg and therefore was not included here in order to avoid circular logic. There is a ClinVar entry for this variant (ClinVar variation ID: 270904, 2 star review status) with 3 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, PP4
Counsyl	RCV000410158	SCV000486333	likely pathogenic	Glycogen storage disease, type II	2016-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410158	SCV000626551	pathogenic	Glycogen storage disease, type II	2023-10-12	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 (rs1800312, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 16860134, 22613277, 29122469). ClinVar contains an entry for this variant (Variation ID: 370904). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000723386	SCV000700286	pathogenic	not provided	2017-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000723386	SCV000890192	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in reduced GAA activity (Nino et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in 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: 26889246, 22613277, 25525159, 23457621, 22252923, 25741864, 26685070, 18519449, 29880332, 29122469, 10206684, 28726123, 33741225, 27655474, 26497565, 16860134, 23430493)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000410158	SCV001422605	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 2 Caucasian and 1 Asian individuals with Glycogen Storage Disease II (PMID: 16860134, 22613277, 25741864), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics, GeneDx, and Invitae in ClinVar (Variation ID: 370904). This variant has been identified in 0.004% (1/24930) of African chromosomes and 0.002% (2/128684) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800312). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with HEK293 cells transfected with this variant provide some evidence that the p.Trp746Ter variant may impact GAA processing and activity (PMID: 23430493). However, these types of assays may not accurately represent biological function. 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 combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 22613277). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in an assay of skin fibroblasts (PMID: 16860134, 22613277). One additional pathogenic variant, c.2237G>A (p.Trp746Ter), with the same position and amino acid change has been reported in association with disease (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254). 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 low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting, PP4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410158	SCV001737657	pathogenic	Glycogen storage disease, type II	2021-05-30	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2238G>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. The variant allele was found at a frequency of 8e-06 in 250832 control chromosomes. c.2238G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Kishnani_2006, Patel_2012, Mori_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal GAA activity as measured following transient expression in HEK293 cells (Nino_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000723386	SCV002023836	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410158	SCV003835792	pathogenic	Glycogen storage disease, type II	2022-10-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000410158	SCV002092118	pathogenic	Glycogen storage disease, type II	2020-10-28	no assertion criteria provided	clinical testing