Submissions for variant NM_000152.5(GAA):c.546G>C (p.Thr182=)

dbSNP: rs143523371

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000361874	SCV000331161	pathogenic	not provided	2015-07-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249018	SCV001422887	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.546G>C (p.Thr182=) variant in GAA has been reported in 1 Spanish individual with Glycogen Storage Disease II (PMID: 17616415), and has also been reported pathogenic by EGL in ClinVar (Variation ID: 281056). This variant has been identified in 0.002% (2/106330) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143523371). 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 is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing. The Threonine (Thr) at position 182 is not well conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the c.546G>C variant is pathogenic (PMID: 17616415). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with only 21% of control GAA activity detected in patient fibroblasts (PMID: 17616415). Two additional variants at the same position, c.546G>T and c.546G>A, have been reported as a VUS or likely pathogenic in association with Glycogen Storage Disease II in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 370637, 280955). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP4, PM3_Supporting, PM5_Supporting (Richards 2015).
Invitae	RCV001249018	SCV001578266	pathogenic	Glycogen storage disease, type II	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.546G nucleotide in the GAA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 14695532, 21484825, 25037089; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 31301153). ClinVar contains an entry for this variant (Variation ID: 281056). This variant has been observed in individual(s) with Pompe disease (PMID: 17616415). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects codon 182 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine.
Revvity Omics, Revvity	RCV000361874	SCV002025195	likely pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000361874	SCV002501909	likely pathogenic	not provided	2021-10-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001249018	SCV002791307	likely pathogenic	Glycogen storage disease, type II	2021-11-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001249018	SCV004197861	pathogenic	Glycogen storage disease, type II	2023-03-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001249018	SCV002091930	pathogenic	Glycogen storage disease, type II	2021-08-24	no assertion criteria provided	clinical testing