Submissions for variant NM_000152.5(GAA):c.877G>A (p.Gly293Arg)

gnomAD frequency: 0.00003  dbSNP: rs121907945

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000578430	SCV002817451	pathogenic	Glycogen storage disease, type II	2022-11-02	reviewed by expert panel	curation	The NM_000152.5:c.877G>A variant in GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 293 (p.Gly293Arg). Patients with a diagnosis of Pompe disease reported with this variant include five individuals with documented laboratory values showing deficient GAA activity meeting the specifications of the ClinGen LSD VCEP (PMIDs: 23566438, 24590251, 26497565), one of whom also has features reported that are consistent with infantile onset Pompe disease (PMID: 31510962) and additional patients reported to be on enzyme replacement therapy but without documentation of residual GAA activity (PMID: 18607768, 21605996) (PP4_Moderate). At least 6 patients are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 18607768, 21605996, 23566438, 24590251, 25455803, 29181627, 31710733), c.2481+102_2646+31del (PMID: 18429042) and c.716del (p.Leu239fsTer28) (PMID: 14695532), and at least two individuals are homozygous for the variant (PMIDs: 31510962, 26497565) (2 x 0.5 points) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and either c.719C>T (p.Phe240Ser; note that reference sequence has a T at position 719) (PMID: 25455803) or c.710C>T (p.Ala237Val) (PMIDs: 15668445, 17573812, 17643989. The allelic data from these patients will be used in the classification of p.Phe240Ser and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00006 (2/35062 alleles) in the Latino / Admixed American population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in <2% residual GAA activity in medium and cells (PMIDs 14695532, 19862843). No GAA protein was observed on Western blot of COS cells expressing the variant (PMID 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.931 which is above the threshold of 0.7, evidence that correlates with impact to GAA function, and SpliceAI predicts the creation of a cryptic splice site 2 nucleotides downstream from the variant (PP3). There is a ClinVar entry for this variant (Variation ID: 4036; 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen LSD VCEP on Nov. 2, 2022)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578430	SCV000680242	pathogenic	Glycogen storage disease, type II	2017-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578430	SCV000825724	pathogenic	Glycogen storage disease, type II	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 293 of the GAA protein (p.Gly293Arg). This variant is present in population databases (rs121907945, gnomAD 0.006%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532, 15668445, 17573812, 18607768, 22676651, 24590251, 27344650, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 4036). 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: 14695532, 19862843). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000728952	SCV000856579	pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000578430	SCV001361534	pathogenic	Glycogen storage disease, type II	2019-07-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.877G>A (p.Gly293Arg) results in a non-conservative amino acid change located in the N-terminal domain (IPR025887) 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 1.6e-05 in 245436 control chromosomes (gnomAD). c.877G>A has been reported in the literature in several compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Muller-Felber_2007, Angelini_2012, Herzog_2012). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a less 10% of normal enzyme activity for the variant protein (Hermans_2004, Flanagan_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of these laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000578430	SCV001422611	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly293Arg variant in GAA has been reported in 8 individuals (including 2 Germans, 2 from the UK, 1 Italian, and 1 Afghan individuals) with Glycogen Storage Disease II (PMID: 14695532, 18429042, 23566438, 15668445, 18607768, 26497565), and has also been reported pathogenic by Invitae, EGL Genetic Diagnostics, OMIM, and Klinikum rechts der Isar in ClinVar (Variation ID: 4036). This variant has been identified in 0.006% (2/35062) of Latino chromosomes, 0.004% (1/24260) of European (non-Finnish) chromosomes, and 0.004% (1/24388) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907945). 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.Gly293Arg variant may impact GAA activity and levels (PMID: 14695532, 19862843). 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 reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly293Arg variant is pathogenic (PMID: 26497565, 23566438). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low levels of GAA activity in leukocytes, muscle, or lymphocytes (PMID: PMID: 26497565, 23566438). 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 the variant and multiple occurrences with reported pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PP4, PM2, PP3 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV000578430	SCV002791718	pathogenic	Glycogen storage disease, type II	2021-09-21	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000578430	SCV003934946	pathogenic	Glycogen storage disease, type II	2023-06-22	criteria provided, single submitter	clinical testing	The homozygous mis-sense variant c.877G>A (p.Gly293Arg) has been identified in a proband with cardiomegaly, cardiomyopathy and respiratory distress. This variant has been found 0.0018%gnomAD (aggregated). This has been previously reported PMID: 31342611
GeneDx	RCV000728952	SCV004023028	pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein function (Hermans et al., 2004; Flanagan et al., 2009); 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 and on splicing; Located in the N-terminal -sandwich domain (Kroos et al., 2012; Sugawara et al., 2009); This variant is associated with the following publications: (PMID: 34530085, 31254424, 30275481, 24590251, 29181627, 27344650, 14695532, 18429042, 15668445, 31606152, 22676651, 31510962, 29122469, 18607768, 17573812, 19862843, 22253258, 19343043)
Baylor Genetics	RCV000578430	SCV004195436	pathogenic	Glycogen storage disease, type II	2024-03-29	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000728952	SCV004934102	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing
OMIM	RCV000004251	SCV000024417	pathogenic	Glycogen storage disease II, adult form	2005-01-25	no assertion criteria provided	literature only