Submissions for variant NM_000152.5(GAA):c.2236T>G (p.Trp746Gly)

gnomAD frequency: 0.00001  dbSNP: rs1479740763

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672437	SCV000797542	uncertain significance	Glycogen storage disease, type II	2018-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672437	SCV001361532	likely pathogenic	Glycogen storage disease, type II	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2236T>G (p.Trp746Gly) 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 was absent in 250780 control chromosomes (gnomAD). c.2236T>G has been reported in the literature in a heterozygous individual, found during newborn screening, who had a low lymphocyte GAA activity (Labrousse 2010). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). At least one publication reports experimental evidence evaluating an impact on protein function (Nino 2012). The most pronounced variant effect results in <10% of normal activity. Two other variants affecting the same codon, namely c.2238G>C (p.Trp746Cys, internal database) and c.2236T>C (p.Trp746Arg, Emory EmVClass variant database) have been reported as Pathogenic and Likely Pathogenic respectively. This suggests that the variant may impact a functionally critical residue in the GAA protein. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS, and pathogenic /likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000672437	SCV001422965	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp746Gly variant in GAA has been reported in two individuals with glycogen storage disease II (PMID: 21488293, 20080426) and has also been reported in ClinVar (VariationID: 556431) as a VUS by Counsyl. Data from large population studies is insufficient to assess the frequency of this variant. In vitro functional studies using HEK-293 cells and medium transfected with the variant provide some evidence that the p.Trp746Gly variant may impact protein function (PMID: 23430493). However, these types of assays may not accurately represent biological function. Three additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Trp746Ser, p.Trp746Cys, and p.Trp746Arg, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 188484, 265160, 499293). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 and multiple reported pathogenic variants in the same codon. ACMG/AMP Criteria applied: PM5_strong, PS3, PP3 (Richards 2015).
Genome-Nilou Lab	RCV000672437	SCV001810182	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784273	SCV002023795	pathogenic	not provided	2019-10-16	criteria provided, single submitter	clinical testing
Invitae	RCV000672437	SCV003442524	likely pathogenic	Glycogen storage disease, type II	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 746 of the GAA protein (p.Trp746Gly). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individual(s) with features of Pompe disease (PMID: 20080426). ClinVar contains an entry for this variant (Variation ID: 556431). 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. 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: 7981676, 9535769, 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.