Submissions for variant NM_000152.5(GAA):c.853C>T (p.Pro285Ser)

gnomAD frequency: 0.00008  dbSNP: rs886042086

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000383868	SCV002032134	likely pathogenic	Glycogen storage disease, type II	2021-12-02	reviewed by expert panel	curation	The NM_000152.5:c.853C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 285 (p.Pro285Ser). The highest population minor allele frequency in gnomAD is 0.00009 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. REVEL (in silico meta predictor for missense changes) score = 0.757 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion. At least two patients had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PP4_Moderate). Two individuals with Pompe disease have been reported who are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown; either c.2237G>A (p.Trp746Ter)(PMID: 21484825)(0.5 points) or c.1354_1372del19 (PMID: 21550241)(0.5 points), Total 1 point (PM3). This variant results in <5% GAA activity when expressed in COS cells, and was classified as Class C ("less severe") by Kroos et al, 2012 (PMID:22644586), meeting the ClinGen LSD VCEP criteria for PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 281052, 1 star review status) with 5 submitters, two classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PP3, PM2_supporting, PM3, PS3_supporting.
Eurofins Ntd Llc (ga)	RCV000723486	SCV000331150	pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000383868	SCV000791139	uncertain significance	Glycogen storage disease, type II	2017-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000383868	SCV000917401	pathogenic	Glycogen storage disease, type II	2018-12-13	criteria provided, single submitter	clinical testing	Variant summary: GAA c.853C>T (p.Pro285Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 27092 control chromosomes. c.853C>T has been reported in the literature in individuals affected with Late Onset Pompe Disease (Bali_2011, Carlier_2011, Kroos_2008, Nallamilli_2018, Orlikowski_2011), and in one reported case the GAA activity in the patients fibroblasts was <1% (Bali_2011). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000383868	SCV001380489	pathogenic	Glycogen storage disease, type II	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the GAA protein (p.Pro285Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 21484825, 21550241). ClinVar contains an entry for this variant (Variation ID: 281052). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). This variant disrupts the p.Pro285 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14695532, 28196920). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000383868	SCV001422621	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Pro285Ser variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 21550241, 21484825, 30564623), and has also been reported as a pathogenic variant by EGL Genetic Diagnostics and Integrated Genetics and a VUS by Counsyl in ClinVar (Variation ID: 281052). This variant has been identified in 0.013% (3/22640) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886042086). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Pro285Ser variant may impact GAA activity and slightly reduce GAA levels (PMID: 22644586). 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. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Pro285Ser variant is pathogenic (PMID: 21550241, 21484825). One additional pathogenic variant at the the same position, p.Pro285Arg, was reported in association with disease, supporting that a change at this position may not be tolerated (Variation ID: 225114). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21550241, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on evidence from in vitro functional studies, low frequency in the general population, and another pathogenic variant reported at the same position. ACMG/AMP Criteria applied: PS3, PM5, PM2, PM3_Supporting, PP3, PP4 (Richards 2015).
Genome-Nilou Lab	RCV000383868	SCV001810462	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000723486	SCV002023835	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000383868	SCV002781007	likely pathogenic	Glycogen storage disease, type II	2021-10-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000383868	SCV004195513	pathogenic	Glycogen storage disease, type II	2023-08-11	criteria provided, single submitter	clinical testing