Submissions for variant NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)

dbSNP: rs752921215

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626060	SCV000746682	likely pathogenic	Glycogen storage disease, type II	2017-12-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000626060	SCV000795205	likely pathogenic	Glycogen storage disease, type II	2017-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000626060	SCV000950050	pathogenic	Glycogen storage disease, type II	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 746 of the GAA protein (p.Trp746Ser). This variant is present in population databases (rs752921215, gnomAD 0.03%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22081099). ClinVar contains an entry for this variant (Variation ID: 188484). 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: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000626060	SCV001422665	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino 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 variant has also been reported as a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). 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 in combination with a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001781520	SCV002025231	pathogenic	not provided	2022-12-20	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001781520	SCV002502344	likely pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001781520	SCV002568586	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(W746S) results in a significant reduction in enzymatic activity (Kroos et al., 2012; Nino et al., 2013); 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: 24444888, 24169249, 18425781, 22644586, 23430493, 29325298, 30275481, 19343043, 22253258, 31589614, 27535533, 34906458, 26582918, 34020684, 33717985, 22081099, Jian2021, 33344388)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000626060	SCV003800659	pathogenic	Glycogen storage disease, type II	2023-01-18	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2237G>C (p.Trp746Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250744 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (6.8e-05 vs 0.0042), allowing no conclusion about variant significance. c.2237G>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Angelini_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics	RCV000626060	SCV003927051	pathogenic	Glycogen storage disease, type II	2023-05-05	criteria provided, single submitter	clinical testing	The classification of the variant was performed according to the recommendations of ClinGen lysosomal storage disorders variant curation expert panel (Guidelines version 2, specific for the GAA gene). The NM_000152.5:c.2237G>C p.(Trp746Ser) is a missense variant that replaces a highly conserved Trp with Ser. This variant is present at a very low frequency in gnomAD databases (ƒExomes = 0.0000678, ƒgenomes = 0.0000854), only in heterozygosity and meets the PM2_Supporting criterion (1pt). This variant is located in a mutational hot-spot sequence of 17 amino-acids length with 20 missense/in-frame variants (8 pathogenic variants, 12 uncertain variants) and without benign variation, which qualifies the c.2237G>C variant as moderate pathogenic (PM1 criterion, 2pts). Five pathogenic alternative variants [Trp746Cys (chr17:78090815G>T and chr17:78090815 G>C), Trp746Leu, Trp746Gly and Trp746Arg] affecting the same amino acid (Trp746) have been reported in association with disease in ClinVar (PM5_strong: 4pts). Multiple lines of computational evidence strongly support the pathogenicity of this variant (REVEL score: 0.919) and therefore meets the PP3 criterion (supporting, 1pt). The c.2237G>C variant confirmed to be in trans with different pathogenic or likely pathogenic variants (PMID: 25526786, PMID: 18429042, PMID: 12923862, PMID: 21484825, PMID: 16917947, PMID: 18285536) in individuals with Pompe disease, thus meets the PM3_very strong criterion (4pts). In vitro functional studies provide evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). In our study, the four individuals (with c.[266G>A];[2237G>C] genotype, 2-13 years) were found to have GAA activity clearly within the patient range (1.1-4.9nmol/h/mg) in leukocytes using 4-methylumbelliferyl-α-D-glucoside as a substrate. Using glycogen as a substrate, the GAA activity was found to be within the range for LOPD patients (3-10nmol/h/mg) for one subject and slightly above the upper limit for the three subjects. The presence of the KM-mutant polymorphism c.271G>A and the pseudodeficiency variant c.[1726G>A (p.Gly576Ser); 2065G>A (p.Glu689Lys)] was excluded. Based on the ClinGen LSD VCEP's specifications, this data meets PP4_Moderate rule (2pts). In summary, this variant meets the criteria to be classified as a pathogenic variant (total 14 pts) for Pompe disease.
Baylor Genetics	RCV000626060	SCV004195498	likely pathogenic	Glycogen storage disease, type II	2023-09-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000626060	SCV001459753	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing