Submissions for variant NM_000152.5(GAA):c.1802C>G (p.Ser601Trp)

dbSNP: rs374470794

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597451	SCV000708291	likely pathogenic	not provided	2017-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199859	SCV001370595	likely pathogenic	Glycogen storage disease, type II	2020-05-01	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1802C>G (p.Ser601Trp) 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 248082 control chromosomes (gnomAD). c.1802C>G has been reported in the literature in individuals (in compound heterozygous state) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Palmer_2007, DeFilippi_2014, Parini_2018). These data indicate that the variant is likely to be associated with disease. Most of the patients from these reports had late onset phenotype of the disease. In in vitro functional studies, the variant was found to have reduced enzymatic activity (Flanagan_2009). One ClinVar submitter (evaluation after 2014) cite the variant as 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	RCV001199859	SCV001422903	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Ser601Trp variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 17056254) and has also been reported likely pathogenic by EGL in ClinVar (Variation ID: 501793). This variant was absent from large population studies. 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 likely pathogenic variant has been reported at the the same position, p.Ser601Leu, slightly supporting that a change at this position may not be tolerated (Variation ID: 194154; PMID: 30023291, 22676651, 22644586). The presence of this variant in combination with a pathogenic variant curated by our study and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser601Trp variant is pathogenic (PMID: 17056254). The phenotype of the individual with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in lymphocytes (PMID: 17056254). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015).
Baylor Genetics	RCV001199859	SCV004197781	pathogenic	Glycogen storage disease, type II	2024-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001199859	SCV004296882	pathogenic	Glycogen storage disease, type II	2023-05-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser601 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22252923, 22644586, 28394184). 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: 501793). This missense change has been observed in individual(s) with Pompe disease (PMID: 17056254, 24158270, 32711049). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 601 of the GAA protein (p.Ser601Trp).