Submissions for variant NM_000152.5(GAA):c.854C>G (p.Pro285Arg)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004017497	SCV000263032	pathogenic	Cardiovascular phenotype	2014-10-08	criteria provided, single submitter	clinical testing	The c.854C>G (p.P285R) alteration is located in exon 4 (coding exon 3) of the GAA gene. The alteration results from a C to G substitution at nucleotide position 854, causing the Proline (P) at amino acid position 285 to be replaced by an Arginine (R). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the GAA c.854C>G alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The amino acid change has been observed in affected individuals: _x000D_ This missense change has been reported in a German patient with late infantile/juvenile onset GSDII (Bodamer, 2002). The patient had this mild P285R mutation in combination with a severe mutation on the other allele. This alteration has also been reported homozygous in an Iranian boy presenting at age 2 with Pompe disease (Nazari, 2017). The altered amino acid is conserved throughout evolution:_x000D_ The p.P285 amino acid position is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.P285R amino acid is located in the N-terminal domain of the GAA protein (Flanagan, 2009). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis demonstrated that the p.P285R alteration resulted in 7-10% residual enzyme activity in vitro (Bodamer, 2002). A subsequent study confirmed partial loss of enzyme activity for glycogen and an artificial substrate classified it as a mild mutation (Hermans, 2004). Flanagan et al. (2009) also determined that the pharmacological chaperone 1-Deoxynojirimycin (DNJ) was able to increase the GAA enzyme activity in fibroblast cells expressing this mutant and may be a potential therapeutic treatment for GSDII patients. The alteration is predicted deleterious by in silico models:_x000D_ The p.P285R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797884	SCV000937469	pathogenic	Glycogen storage disease, type II	2022-11-01	criteria provided, single submitter	clinical testing	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: 21484825, 21550241). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 285 of the GAA protein (p.Pro285Arg). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 28196920). ClinVar contains an entry for this variant (Variation ID: 225114). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000797884	SCV001423075	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Pro285Arg variant in GAA has been reported in at least 3 individuals (including 1 German individual) with Glycogen Storage Disease II (PMID: 14695532, 12213618, 28196920; DOI: 10.1016/S1472-6483(16)30370-4), and has also been reported pathogenic by Ambry Genetics and as a VUS by Invitae in ClinVar (Variation ID: 225114). This variant has been identified in 0.001% (1/87084) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764622267). 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.Pro285Arg variant may impact GAA activity (PMID: 14695532, 19862843, 12213618). 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.Pro285Arg variant is pathogenic (PMID: 14695532, 12213618). One pathogenic variant at the same position, p.Pro285Ser, has been reported in association with Glycogen Storage Disease II (Variation ID: 281052). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity in their leukocytes or fibroblasts and no known pseudodeficiency alleles in at least one individual (PMID: 28196920, 12213618). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant, individuals with phenotypes highly specific for Glycogen Storage Disease II, and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PP4_Moderate, PM3_Supporting, PM2, PP3 (Richards 2015).
Baylor Genetics	RCV000797884	SCV004195432	pathogenic	Glycogen storage disease, type II	2023-10-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003488466	SCV004238200	likely pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing

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