Submissions for variant NM_000152.5(GAA):c.1556T>C (p.Met519Thr)

gnomAD frequency: 0.00001  dbSNP: rs786204720

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169538	SCV000221019	likely pathogenic	Glycogen storage disease, type II	2015-01-14	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000726790	SCV000703062	uncertain significance	not provided	2016-11-02	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169538	SCV001422666	likely pathogenic	Glycogen storage disease, type II	2020-01-29	criteria provided, single submitter	curation	The p.Met519Thr variant in GAA has been reported in 3 individuals (1 Australian, 1 Dutch, and 1 Belgian) with Glycogen Storage Disease II (PMID: 14695532), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.001% (1/113600) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786204720). 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 likely pathogenic by Counsyl and a VUS by EGL in ClinVar (Variation ID: 189124). This variant is located in the highly conserved GH31 motif, a region involved in substrate binding (PMID: 19862843, 15501829). In vitro functional studies provide some evidence that the p.Met519Thr variant may impact protein function (PMID: 19862843, 14695532). 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. One additional variant at the the same position, p.Met519Val, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 19862843, 14695532). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PM5_Supporting (Richards 2015).
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000169538	SCV001438025	pathogenic	Glycogen storage disease, type II	2020-10-15	criteria provided, single submitter	clinical testing	Met519Thr has been reported by Reuser et. al. 1995 PMID:7603530
Genome-Nilou Lab	RCV000169538	SCV001810611	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
3billion	RCV000169538	SCV002520969	pathogenic	Glycogen storage disease, type II	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is in trans with NM_000152.5:c.1561G>A variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189124). Different missense changes at the same codon (p.Met519Ile, p.Met519Val) have been reported to be associated with GAA related disorder (ClinVar ID: VCV001067893 / PMID: 31965297, 7866409). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000169538	SCV003443320	pathogenic	Glycogen storage disease, type II	2023-09-04	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met519 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31439017, 31965297; Invitae). 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: 189124). This missense change has been observed in individual(s) with Pompe disease (PMID: 31086307, 33741225). This variant is present in population databases (rs786204720, gnomAD 0.003%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 519 of the GAA protein (p.Met519Thr).
Revvity Omics, Revvity	RCV000726790	SCV003816186	likely pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000169538	SCV004176385	pathogenic	Glycogen storage disease, type II	2023-02-14	criteria provided, single submitter	clinical testing	The missense variant c.1556T>C(p.Met519Thr) in GAA gene has been reported in homozygous state in individuals with Pompe disease (Puri RD, et al., 2021).Experimental studies have shown that this missense change affects GAA function. This variant disrupts the p.Met519 amino acid residue in GAA (Flanagan JJ,et al., 2009). The variant has 0.001% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain significance/ Likely Pathogenic/ Pathogenic.The amino acid Methionine at position 519 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Met519Thr in GAA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169538	SCV004197879	likely pathogenic	Glycogen storage disease, type II	2022-12-17	criteria provided, single submitter	clinical testing