Submissions for variant NM_000152.5(GAA):c.2173C>T (p.Arg725Trp)

gnomAD frequency: 0.00003  dbSNP: rs121907938

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169045	SCV004227911	pathogenic	Glycogen storage disease, type II	2023-10-03	reviewed by expert panel	curation	The NM_000152.5:c.2173C>T variant in GAA is a missense variant predicted to cause substitution of Arg by Trp at amino acid 725 (p.Arg725Trp). This variant is present in gnomAD V2.1.1 with the highest population minor allele frequency of 0.00077 (7/9058 alleles) in the Ashkenazi Jewish population, which is lower than the ClinGen LSD VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.909 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. This variant results in 6.5% GAA activity when expressed in COS cells (PMID: 8401535), meeting the ClinGen LSD VCEP specifications for PS3. This variant has been detected in at least 12 individuals with Pompe disease. Of those individuals, 10 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant including 2 with c.573C>A-pathogenic (PMID: 30155607), 1 with ex18 deletion-pathogenic (PMID: 28648663), 3 with c.-32-13T>G-pathogenic (PMID: 27711114, 17616415), 1 with c.-32-3C>A-likely pathogenic (PMID: 19588081), 2 with c.1076-1G>C pathogenic variants (PMID: 17616415). 1 individual was homozygous for the variant (PMID: 27711114). A total of 4.25 points were awarded. Thus meets PM3-Very Strong. At least 4 individuals have been reported with this variant and GAA activity <10% normal in leukocytes/muscle samples or <30% normal in cultured fibroblasts. Patient 5 (PMID: 21550241) has 0.2% normal GAA activity in fibroblast. Patient 3 has 1.1% normal GAA activity in fibroblasts, patient 15 has 5.2% normal GAA activity in fibroblasts (PMID: 17616415). Patient 1 (PMID: 3865697) has GAA activity in affected range in muscle, cultured fibroblasts, and leucocytes when compared to the laboratory’s control range. This meets the criteria for PP4. There is a ClinVar entry for this variant (Variation ID: 4024; 2 star review status) with 9 submitters classifying the variant as pathogenic with no conflict. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PS3-supporting, PM2-supporting, PM3-very strong, PP3, and PP4-moderate. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169045	SCV000695648	pathogenic	Glycogen storage disease, type II	2016-12-15	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.2173C>T (p.Arg725Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/44258 control chromosomes at a frequency of 0.0000226, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in at least 5 patients with Pompe disease (3 juvenile and 2 adult). Functional studies showed GAA p.R725W had less than 10% residual activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000169045	SCV000939765	pathogenic	Glycogen storage disease, type II	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 725 of the GAA protein (p.Arg725Trp). This variant is present in population databases (rs121907938, gnomAD 0.08%). This missense change has been observed in individual(s) with Pompe disease (PMID: 8401535, 17616415, 19588081, 21550241, 28648663). ClinVar contains an entry for this variant (Variation ID: 4024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 8401535, 21972175). This variant disrupts the p.Arg725 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 18458862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169045	SCV001422653	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Arg725Trp variant in GAA has been reported in 6 individuals (including 3 Spanish and 1 Brazilian individuals) in the compound heterozygous state with Glycogen Storage Disease II (PMID: 21550241, 8401535, 17616415, 19588081). This variant has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics, Invitae, and OMIM in ClinVar (Variation ID: 4024). This variant has been identified in 0.077% (7/9058) of Ashkenazi Jewish chromosomes and 0.002% (2/104918) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907938). 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 HEK and COS cells provide some evidence that the p.Arg725Trp variant may impact GAA activity (PMID: 21972175, 8401535). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant confirmed in trans with a pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg725Trp variant is pathogenic (PMID: 8401535). The phenotype of heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in relevant tissues (PMID: 17616415, 8401535, 21550241). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with transfected cells and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
GeneDx	RCV001569366	SCV001793430	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (Hermans MM et al., 1993; Ebrahim HY et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17616415, 28648663, 8401535, 19588081, 21550241, 31589614, 35302691, 19343043, 22253258, 31254424, 31342611, 22252923, 27711114, 34530085, 21972175)
Revvity Omics, Revvity	RCV001569366	SCV002023838	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169045	SCV002805487	pathogenic	Glycogen storage disease, type II	2022-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169045	SCV004197791	likely pathogenic	Glycogen storage disease, type II	2023-07-15	criteria provided, single submitter	clinical testing
OMIM	RCV000004239	SCV000024405	pathogenic	Glycogen storage disease II, adult form	1993-01-01	no assertion criteria provided	literature only
Counsyl	RCV000169045	SCV000220203	pathogenic	Glycogen storage disease, type II	2018-09-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169045	SCV002092107	pathogenic	Glycogen storage disease, type II	2020-09-03	no assertion criteria provided	clinical testing