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

gnomAD frequency: 0.00002  dbSNP: rs28937909

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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
Invitae	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	2023-05-16	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