Submissions for variant NM_000152.5(GAA):c.1927G>A (p.Gly643Arg)

gnomAD frequency: 0.00002  dbSNP: rs28937909

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000409137	SCV005089709	pathogenic	Glycogen storage disease, type II	2024-06-06	reviewed by expert panel	curation	The NM_000152.5:c.1927G>A variant in GAA is predicted to result in the substitution of glycine by arginine at amino acid 643 (p.Gly643Arg). Numerous individuals have been reported with this variant and specific features of Pompe disease including GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts/ in the affected range in a clinically validated dried blood spot assay; patients with specific features of infantile onset Pompe disease (including cardiac features and hypotonia_, and on enzyme replacement therapy (PMIDs: 8401535, 17723315, 23430912, 23609349 24158270, 25783438, 26349193, 26497565) (PP4_Moderate). The variant has been reported in patients with Pompe disease who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP. In these cases, the second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (at least 10 cases; maximum 2 x 0.5 points; PMID: 16917947, 18607768, 20308911, 23609349, 24158270, 25396301, 25783438, 27862019, 30155607), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1 (2 cases, 2 x 0.5 points) (PMID: 18429042, 23430912), c.1064T>C (p.Leu355Pro) (ClinVar Variation ID: 284093, SCV001371747.2) (0.5 points, PMID: 18429042), c.236_246del (p.Pro79fsTer) (ClinVar Variation ID: 371302, SCV001443298.1 (0.5 points, PMID: 19588081), and c.2662G>T (p.Glu888Ter) (ClinVar Variation ID: 578595, SCV001371767.1 (0.5 points, PMID: 28394184). First cousins have been reported who are compound heterozygous for the variant (inherited from their heterozygous mothers who are sisters) and another pathogenic variant in GAA variant; c.1655T>C (p.Leu552Pro) (ClinVar Variation ID: 279811, SCV001371750.2) in one individual, and "deletion of exon 18" in the other individual (PMID: 26349193). In each case, the second variant was shown to be inherited from the father. Although the genotypes are different, only one case will be counted from this family, as they are related (1 point, pathogenic variant confirmed in trans). At least 2 cases are homozygous for the variant (max 2 x 0.5 points, PMID: 18429042, 24002816, 26497565, 30023291). Additional cases are compound heterozygous for the variant and either c.2040G>A (PMID: 17723315) or c.2173C>T (p.Arg725Trp) (PMID: 8401535). The in trans data for these patients was used in the classification of the other variant as is not included here to avoid circular logic. Finally, the variant is reported in other cases and publications without sufficient evidence to apply PM3 (PMID:9521422, 17915575, 19862843, 22081099, 29880332) Additional cases may be available in the literature but PM3 is already applied at very strong (>5 points) (PM3_VeryStrong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003667 (4/109080 alleles) in the European non-Finnish population. In gnomAD v4.1, the MAF is 0.00003224 (40/1178798 alleles) in the European non-Finnish population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The activity of this variant, when expressed in COS cells, has been analyzed in several studies (PMIDs: 8401535, 9521422, 19862843) and varies from <2%-6% with 4MUG and ~3% wild type activity in cells with glycogen. Pulse chase analysis showed that the protein is abnormally processed, with most of the protein remaining as precursor (PMID: 8401535) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 4023). 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 Lysosomal Diseases VCEP: PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)
Counsyl	RCV000409137	SCV000485382	pathogenic	Glycogen storage disease, type II	2016-09-09	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788193	SCV000927226	pathogenic	not provided	2017-04-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409137	SCV000937212	pathogenic	Glycogen storage disease, type II	2023-12-14	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 643 of the GAA protein (p.Gly643Arg). This variant is present in population databases (rs28937909, gnomAD 0.004%). This missense change has been observed in individual(s) with Pompe disease (PMID: 8401535, 18607768, 24158270). ClinVar contains an entry for this variant (Variation ID: 4023). 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: 8401535). 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.
Mendelics	RCV000409137	SCV001140842	pathogenic	Glycogen storage disease, type II	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409137	SCV001338528	pathogenic	Glycogen storage disease, type II	2020-04-17	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1927G>A (p.Gly643Arg) results in a non-conservative amino acid change in 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 2.5e-05 in 242074 control chromosomes. c.1927G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; eg. Hermans_1993, Laforet_2000, McCready_2007, Oba-Shinjo_2009, Pittis_2008). Experimental evidence has shown the variant to result in impairment of intracellular transport and maturation of the protein, resulting in severe enzyme deficiency (Hermans_1993) Four 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000409137	SCV001423065	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly643Arg variant in GAA has been reported in the homozygous and heterozygous state in at least 31 individuals (including 8 Italian, 7 French, 3 Brazilian, 1 German, 1 from the UK, 1 Argentinian, 1 Canadian, and 1 Saudi Arabian individuals) with Glycogen Storage Disease II (PMID: 30023291, 25052852, 17056254, 25783438, 30155607, 26349193, 11071489, 20559845, 26497565, 19588081, 18607768, 19862843, 18429042, 17723315, 16917947, 9521422, 8401535), and has also been reported pathogenic by Invitae, Counsyl, Blueprint Genetics, and OMIM in ClinVar (Variation ID: 4023). This variant has been identified in 0.004% (4/109080) of European (non-Finnish) chromosomes, 0.003% (1/29618) of South Asian chromosomes, and 0.003% (1/33956) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28937909). 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 the variant and structural analysis provide some evidence that the p.Gly643Arg variant may impact the GAA active site, GAA processing, and GAA activity (PMID: 19862843, 9521422, 8401535, 25103075). 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 the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly643Arg variant is pathogenic (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues (PMID: 24158270, 17056254, 17723315, 11071489, 26497565). 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, and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV000788193	SCV001502248	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	GAA: PM3:Very Strong, PM2, PP3
Revvity Omics, Revvity	RCV000788193	SCV002023830	pathogenic	not provided	2023-03-16	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000409137	SCV002583239	pathogenic	Glycogen storage disease, type II	2022-06-28	criteria provided, single submitter	clinical testing	A homozygous missense variation in exon 14 of the GAA gene that results in the amino acid substitution of Arginine for Glycine at codon 643 was detected. The observed variant c.1927G>A (p.Gly643Arg) has not been reported in the 1000 genomes and has a MAF of 0.002% in the gnomAD databases. The in silico prediction of the variant is by DANN, LRT, MutationTaster, SIFT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV000409137	SCV002758772	pathogenic	Glycogen storage disease, type II	2022-06-20	criteria provided, single submitter	clinical testing	The c.1927G>A (p.Gly643Arg) in compound heterocigosity with c.-32-13T>G GAA variant has been reported in our laboratory in a 15-year-old boy with diagnosis of Pompe disease (onset 13 years old) with no family history and alpha-1,4-glucosidase lysosomal enzyme activity study: 0,47 µmol/L/h (ref. values: 0.75-5.0). Pompe Variant Database describes this phenotype in seven patients, with age of onset and variable phenoty. It has been previously reported in patients with Pompe disease both in the homozygous and heterozygous state (PMID: 30023291, 25052852, 17056254, 25783438, 30155607, 26349193, 11071489, 20559845, 26497565, 19588081, 18607768, 19862843, 18429042, 17723315, 16917947, 9521422, 8401535). This variant is present in population databases (gnomAD allele frequency 0.00002476). ClinVar contains an entry for this variant (Variation ID: 4023) with no conflicts. Experimental evidence has shown the variant to result in impairment of intracellular transport and maturation of the protein, resulting in severe enzyme deficiency (PMID: 8401535). In summary, c.1927G>A (p.Gly643Arg) GAA variant meets our criteria to be classified as pathogenic for Pompe disease in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals.
Fulgent Genetics, Fulgent Genetics	RCV000409137	SCV002810405	pathogenic	Glycogen storage disease, type II	2022-05-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409137	SCV004197834	pathogenic	Glycogen storage disease, type II	2024-03-13	criteria provided, single submitter	clinical testing
OMIM	RCV000004238	SCV000024404	pathogenic	Glycogen storage disease II, adult form	1993-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000409137	SCV002092081	pathogenic	Glycogen storage disease, type II	2020-08-19	no assertion criteria provided	clinical testing