Submissions for variant NM_000152.5(GAA):c.1940G>T (p.Cys647Phe)

dbSNP: rs1265892085

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001866229	SCV004809070	uncertain significance	Glycogen storage disease, type II	2024-02-06	reviewed by expert panel	curation	The NM_000152.5:c.1940G>T variant in GAA is a missense variant predicted to cause substitution of cysteine by phenylalanine at amino acid 647 (p.Cys647Phe). One case identified by newborn screening with documented deficiency of GAA activity has been reported with this variant, but the symptoms are not highly specific for Pompe disease (PMID: 37087815, clinical laboratory data) (PP4 not met). This patient is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027), with unknown phase (PM3_supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.908 which is above the thresholds predicting a damaging (>0.7) evidence that correlates with impact to GAA function (PP3). Another missense variant c.1941C>G (p.Cys647Trp) (ClinVar Variation ID: 550327) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 1219617). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease, based on the specifications of the ClinGen Lysosomal Disease VCEP. GAA-specific ACMG/AMP specifications met, (Specifications Version 2.0): PM5, PM3_supporting, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Feb 6, 2024).
GeneDx	RCV001588706	SCV001824396	likely pathogenic	not provided	2019-12-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866229	SCV002304955	likely pathogenic	Glycogen storage disease, type II	2021-12-07	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Cys647 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7981676, 9535769, 17723315, 19588081, 22658377, 25681614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1219617). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 647 of the GAA protein (p.Cys647Phe).
Revvity Omics, Revvity	RCV001588706	SCV003816181	uncertain significance	not provided	2019-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699435	SCV005203904	uncertain significance	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1940G>T (p.Cys647Phe) results in a non-conservative amino acid change located in the glycoside hydrolase family 31, TIM barrel domain of 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 273916 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1940G>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1941C>G, p.Cys647Trp), supporting the critical relevance of codon 647 to GAA protein function. ClinVar contains an entry for this variant (Variation ID: 1219617). Based on the evidence outlined above, the variant was classified as uncertain significance.