Submissions for variant NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)

dbSNP: rs535644999

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000631097	SCV004809074	uncertain significance	Glycogen storage disease, type II	2024-03-05	reviewed by expert panel	curation	The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID: 21484825, 28302345). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 188480). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024).
GeneDx	RCV000493868	SCV000582900	uncertain significance	not provided	2018-10-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the GAA gene. The D459N variant in the GAA gene has previously been reported in association with late-onset Pompe disease in individuals who harbored a second missense variant in GAA, although the phase of these variants was not determined in these individuals (Wan et al., 2008; Yang et al., 2011, Bali et al., 2011). This variant is observed in 16/245730 (0.0065%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the D459N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Eurofins Ntd Llc (ga)	RCV000493868	SCV000702471	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631097	SCV000752090	pathogenic	Glycogen storage disease, type II	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 459 of the GAA protein (p.Asp459Asn). This variant is present in population databases (rs535644999, gnomAD 0.04%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18458862, 21484825, 21757382). ClinVar contains an entry for this variant (Variation ID: 188480). 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%. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000631097	SCV000798024	uncertain significance	Glycogen storage disease, type II	2018-02-20	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000631097	SCV001422900	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Asp459Asn variant in GAA has been reported in 3 individuals (including 1 individual from China and 1 individual from Taiwan individual) with Glycogen Storage Disease II (PMID: 18458862, 21484825, 21757382), and has been reported as a VUS by EGL, Invitae, GeneDx, and Counsyl in ClinVar (Variation ID: 188480). This variant has been identified in 0.041% (14/34538) of Latino chromosomes, 0.005% (1/18370) of East Asian chromosomes, and 0.003% (3/112916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs535644999). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional computational prediction tools suggest the variant affects protein structure and stability (PMID: 29061980). However, the Aspartate (Asp) at position 459 is highly conserved in mammals and evolutionary distant species and one additional variant at the same position (p.Asp459His) has been reported as a VUS in ClinVar (Variation ID: 497673), raising the possibility that a change at this position may not be tolerated. The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in assays of relevant tissue (PMID: 18458862, 21757382). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP4 (Richards 2015).
Genome-Nilou Lab	RCV000631097	SCV002027268	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469040	SCV002765934	uncertain significance	not specified	2022-11-30	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1375G>A (p.Asp459Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250268 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (7.2e-05 vs 0.0042), allowing no conclusion about variant significance. c.1375G>A has been reported in the literature in multiple individuals affected with late onset Glycogen Storage Disease, Type 2 (Pompe Disease) (examples: Wan_2008, Bali_2011, Yang_GAA_2011 and Sawada_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV000493868	SCV003828485	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000631097	SCV004195440	pathogenic	Glycogen storage disease, type II	2024-03-02	criteria provided, single submitter	clinical testing
Lildballe Lab, Aarhus University Hospital	RCV000631097	SCV005200605	likely pathogenic	Glycogen storage disease, type II	2024-03-01	criteria provided, single submitter	research	PS1(m), PM5(m), PM2(sup), PM1 (sup)
Fulgent Genetics, Fulgent Genetics	RCV000631097	SCV005653201	likely pathogenic	Glycogen storage disease, type II	2024-01-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000631097	SCV001455612	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing