Submissions for variant NM_000152.5(GAA):c.868A>G (p.Asn290Asp)

gnomAD frequency: 0.00002  dbSNP: rs552929702

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000631072	SCV002817443	uncertain significance	Glycogen storage disease, type II	2024-04-16	reviewed by expert panel	curation	The NM_000152.5:c.868A>G variant in GAA is predicted to result in the substitution of asparagine by aspartate at amino acid 290 (p.Asn290Asp). It has been identified in six individuals by newborn screening, none with clinical features consistent with Pompe disease (PMID: 32064362, 37414610; Essawi et al. 2021, Egypt J Med Hum Genet 22:87). Four of these individuals are homozygous for the variant and have African ancestry (PMID: 37414610), and two patients are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.2105G>A (p.Arg702His), phase unconfirmed, (ClinVar Variation ID: 426278, SCV004809068.1) (PMID: 32064362) or c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160, SCV002032122.1). In the latter, patient, the variants were confirmed to be in trans, and the father, who was described as "completely normal" but with reduced GAA activity, is homozygous for c.868A>G (p.Asn290Asp). Additional cases have been reported (PMID: 22644586, 33073007) but the second variant and clinical details were not provided. Due to the lack of evidence for clinical symptoms in the patients with this variant, PP4 and PM3 were not applied. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00004 (1/24356, no homozygotes) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 71% GAA activity in cells and 38% in medium, with synthesis and processing on Western blot (BS3_Supporting). The computational predictor REVEL gives a score of 0.561 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: 498117). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 21, 2022. Since then, the data for this variant have been re-evaluated and new data have been included but the classification remains the same. The classification of variant of uncertain significance was reapproved on April 16, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, BS3_Supporting.
Eurofins Ntd Llc (ga)	RCV000598383	SCV000702967	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631072	SCV000752065	pathogenic	Glycogen storage disease, type II	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 290 of the GAA protein (p.Asn290Asp). This variant is present in population databases (rs552929702, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. To date, this missense change has only been observed in individual(s) with abnormal newborn screening for Pompe disease (PMID: 32064362; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498117). 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%. This variant disrupts the p.Asn290 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 22081099; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526979	SCV001737770	uncertain significance	not specified	2021-06-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.868A>G (p.Asn290Asp) results in a conservative amino acid change located in the Glycoside hydrosylase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although this variant is listed as "non-pathogenic" in the Pompe disease database without any supporting clinical evidence, to our knowledge, no occurrence of c.868A>G in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000631072	SCV002027245	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000598383	SCV002541441	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	PM2
Revvity Omics, Revvity	RCV000598383	SCV003810592	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000598383	SCV004169194	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	Identified with a second variant in the GAA gene in an asymptomatic infant with reduced alpha-glucosidase activity on newborn screening; the variant was apparently homozygous in the father who was clinically asymptomatic, but had significantly reduced alpha-glucosidase activity (Mona Essawi et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22253258, 19343043, 22644586, 32064362, 37414610, Essawi2021)
Natera, Inc.	RCV000631072	SCV002091974	uncertain significance	Glycogen storage disease, type II	2020-02-13	no assertion criteria provided	clinical testing