Submissions for variant NM_000152.5(GAA):c.2105G>A (p.Arg702His)

gnomAD frequency: 0.00003  dbSNP: rs398123172

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000541873	SCV004809068	pathogenic	Glycogen storage disease, type II	2024-03-05	reviewed by expert panel	curation	The NM_000152.5:c.2105G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 702 (p.Arg702His). At least 3 unrelated patients were noted to have deficient GAA activity but results were not provided (PMID: 26310554, 30897595, 28394184). Two patients are described as having IOPD with clinical symptoms consistent with IOPD reported in one (PMID: 26310554). One patient is described as having juvenile-onset Pompe disease with deficient GAA (value not provided) (PMID: 18211760). Another patient is reported to have deficient GAA and late-onset Pompe disease (PMID: 30897595) (PP4_Moderate). At least one patient is described as having this variant in trans with a variant classified as likely pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (c.796C>T, p.Pro266Ser; ClinVar Variation ID Variation ID: 556117; SCV002540664.1) (PMID: 18211760). At least two patients have been reported with this variant in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen LD VCEP (c.2297A>C, p.Tyr766Ser, ClinVar Variation ID: Variation ID: 420102, SCV002540647.1, and c.2238G>C, p.Trp746Cys, ClinVar Variation ID: Variation ID: 265160, SCV002032122.1), phase unconfirmed for both (PMID: 28394184 and 30897595) (PM3_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 cells resulted in 5% wild type GAA activity in medium and 13% residual activity in cells with evidence of abnormal synthesizing and processing (PMID: 18425781) leading the variant to be described as Class D “potentially mild” indicating that this variant may impact protein function (PS3_supporting). Another missense variant (c.2105G>T, p.Arg702Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (ClinVar Variation ID: Variation ID: 92472)(PM5). There is a ClinVar entry for this variant (Variation ID: 426278). In summary, this variant meets the criteria to be classified as pathogenic 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): PM3_strong, PM5, PP4_moderate, PM2_supporting, PP3, PS3_supporting.
GeneDx	RCV000489782	SCV000576679	pathogenic	not provided	2024-08-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect leading to significantly reduced but not absent enzyme activity compared to wild-type (PMID: 18425781); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26310554, 31254424, 30275481, 18425781, 18211760, 27344650, 29325298, 31342611, 30526868, 32064362, 22253258, 19343043, 34426522, 28394184, 38186848, 30897595, 39010129)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541873	SCV000626543	pathogenic	Glycogen storage disease, type II	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the GAA protein (p.Arg702His). This variant is present in population databases (rs398123172, gnomAD 0.009%). This missense change has been observed in individuals with Pompe disease (PMID: 18211760, 26310554, 28394184). ClinVar contains an entry for this variant (Variation ID: 426278). 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: 18425781). This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14972326, 22252923, 24158270, 27344650, 29122469). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000541873	SCV000695647	pathogenic	Glycogen storage disease, type II	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.2105G>A (p.Arg702His) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/248554 control chromosomes in genomAD at a frequency of 0.0000523, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple Pompe pts. Functional study showed deficient enzyme activity, and variant was classified as a mild pathogenic mutation (Kroos_2008) . In addition, one other clinical diagnostic laboratory classified this variant as pathogenic. Variant involving the same codon Arg702Cys has been reported in affected individuals suggesting functional importance of this location. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000489782	SCV000709614	likely pathogenic	not provided	2017-06-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000541873	SCV001422652	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Arg702His variant in GAA has been reported in 4 individuals (3 Chinese and 1 Turkish/Dutch individuals) with Glycogen Storage Disease II (PMID: 28394184, 18211760, 26310554, 18425781). This variant has also been reported pathogenic by GeneDx, Integrated Genetics, and Invitae and likely pathogenic by EGL Genetic Diagnostics and Counsyl in ClinVar (Variation ID: 426278). This variant has been identified in 0.009% (2/22334) of African chromosomes, 0.008% (9/114642) of European (non-Finnish) chromosomes, and 0.007304% (2/27382) South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123172). 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 provide some evidence that the p.Arg702His variant may impact enzyme levels and activity (PMID: 18425781). 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. This variant was reported in combination with a likely pathogenic variant and in individuals with Glycogen Storage Disease II (PMID: 28394184, 18211760). Two additional variants at the the same position, p.Arg702Cys and p.Arg702Leu, have been reported likely pathogenic or pathogenic in association with disease in the literature and ClinVar or curated by our study, supporting that a change at this position may not be tolerated (PMID: 28394184, 27344650, 24158270, 14972326; Variation ID: 92472). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PS3_Moderate, PM2, PP3 (Richards 2015).
Revvity Omics, Revvity	RCV000489782	SCV002025232	likely pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000541873	SCV002060348	likely pathogenic	Glycogen storage disease, type II	2021-10-01	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.2105G>A(R702H) is a missense variant classified as likely pathogenic in the context of Pompe disease. R702H has been observed in cases with relevant disease (PMID: 18425781, 18211760, 28394184, 26310554, 27344650, 30897595, 29325298). Functional assessments of this variant are available in the literature (PMID: 18425781). R702H has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000152.3(GAA):c.2105G>A(R702H) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000541873	SCV002780044	pathogenic	Glycogen storage disease, type II	2021-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000541873	SCV004195484	pathogenic	Glycogen storage disease, type II	2024-03-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000541873	SCV001459748	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000489782	SCV001932375	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000489782	SCV001953069	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003962356	SCV004781929	likely pathogenic	GAA-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The GAA c.2105G>A variant is predicted to result in the amino acid substitution p.Arg702His. This variant has been reported with a second GAA variant in individuals with glycogen storage disease II (see, for example, Kroos et al. 2008. PubMed ID: 18425781; Chen X et al 2017. PubMed ID: 28394184; Lyu et al. 2019. PubMed ID: 30897595). In vitro experimental studies suggest this variant has a mild impact on protein function (Kroos et al. 2008. PubMed ID: 18425781). Alternative amino acid changes at this position (p.Arg702Cys, p.Arg702Leu) have also been reported in individuals with glycogen storage disease II (Montalvo et al. 2004. PubMed ID: 14972326; Bali et al. 2012. PubMed ID: 22252923). This variant is reported in 0.0090% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78087081-G-A). This variant is interpreted as likely pathogenic.