Submissions for variant NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)

gnomAD frequency: 0.00001  dbSNP: rs536906561

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169262	SCV001371752	pathogenic	Glycogen storage disease, type II	2023-07-03	reviewed by expert panel	curation	The NM_000152.5:c.1942G>A (p.Gly648Ser) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (10/29720 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 18 patients with a diagnosis of Pompe disease have been reported with this variant including those with documented deficient GAA activity and/or symptoms consistent with infantile onset Pompe disease and/or on enzyme replacment therapy (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962) (PP4_Moderate). In a study of the Maroon population of French Guiana, 9 out of 15 probands with "enzymatically confirmed" infantile onset Pompe disease were compound heterozygous for c.1942G>A (p.Gly648Ser) and c.2560C>T (p.Arg854Ter), a variant which has been classified as pathogenic by the ClinGen LD VCEP. The two variants are assumed to be in trans based on the high carrier frequency of both variants in that population. The carrier frequency of c.1942G>A (p.Gly648Ser) was 1 in 47 (9/425 women tested) (PMID: 29637184). Patients have also been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.2214G>A (p.Trp768Ter) (PMID: 26575883) and c.-32-13T>G (2 patients, PMIDs: 17643989, 25455803, 27193587). In addition, at least 3 patients are homozygous for the variant (PMID: 26497565, 29122469, 29889338, 30214072) (PM3_VeryStrong). Patients compound heterozygous for the variant and c.1076-22T>G (17643989, 25455803), c.2646+2T>A (PMID: 29422078), and c.1099T>C (p.Trp367Arg) (PMID: 31510962) have also been reported. However, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid circular logic. When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was "negligible" (PMID: 9535769), and when expressed in COS cells, the variant resulted in <2% wild type GAA activity (PMID: 19862843) (PS3_Supporting). The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function (PP3). Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID: 188902). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023)
Counsyl	RCV000169262	SCV000220552	likely pathogenic	Glycogen storage disease, type II	2014-07-24	criteria provided, single submitter	literature only
Invitae	RCV000169262	SCV000626535	pathogenic	Glycogen storage disease, type II	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 648 of the GAA protein (p.Gly648Ser). This variant is present in population databases (rs536906561, gnomAD 0.03%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 9535769, 17643989, 26575883). 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: 188902). 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: 9535769, 19862843). This variant disrupts the p.Gly648 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 22644586, 23146291), 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	RCV000169262	SCV001361272	pathogenic	Glycogen storage disease, type II	2019-01-07	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1942G>A (p.Gly648Ser) results in a non-conservative amino acid change in the Glycoside hydrolase superfamily (IPR017853) 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 5.5e-05 in 237998 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (5.5e-05 vs 0.0042), allowing no conclusion about variant significance. c.1942G>A has been reported in the literature in multiple individuals affected with adult onset and infantile onset Glycogen Storage Disease, Type 2 (Pompe Disease)(Huie_1998, Elenga_2018). A patient diagnosed with adult onset Pompe Disease was observed to have <10% enzyme activity in vivo. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite 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	RCV000169262	SCV001423120	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly648Ser variant in GAA has been reported in 15 individuals with Glycogen Storage Disease II (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769), and has also been reported pathogenic by Invitae and likely pathogenic by Counsyl in ClinVar (Variation ID: 188902). This variant has been identified in 0.034% (10/29720) of South Asian chromosomes in gnomAD chromosomes in gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs536906561). 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.Gly648Ser variant may impact GAA activity (PMID: 9535769). 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.Gly648Ser variant is pathogenic (PMID: 29637184, 17573812, 26497565, 17643989, 25455803, 9535769). Individuals with this variant in the homozygous and heterozygous state and a phenotype highly specific for disease based on assays of GAA activity in relevant tissue (PMID: 29637184, 17573812, 26497565, 9535769). One additional likely pathogenic variant resulting in a different amino acid change at the same position, p.Gly648Asp, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22644586). 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 and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PM5_Supporting, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001781523	SCV002023819	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing
Arcensus	RCV000169262	SCV002564595	pathogenic	Glycogen storage disease, type II	2013-02-01	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000169262	SCV003926534	pathogenic	Glycogen storage disease, type II	2023-04-25	criteria provided, single submitter	clinical testing	A Heterozygous variation in exon 14 of the GAA gene that results in the amino acid substitution of serine for glycine at codon 648 was detected. The observed variant c.1942G>A (p.Gly648Ser) has not been reported in the 1000 genomes database and this variant has minor allele frequency of 0.0054% in gnomAD database. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, CAAD and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000169262	SCV003934921	pathogenic	Glycogen storage disease, type II	2023-06-22	criteria provided, single submitter	clinical testing	The homozygous mis-sense variant c.1942G>A (p.Gly648Ser) has been identified in a proband with dilated cardiomyopathy, respiratory distress, muscle weakness, difficulty in sitting from lying position, proximal muscle weakness in upper and lower extremities. This variant has been found 0.0054%gnomAD (aggregated). This has been previously reported PMID: 18429042
Baylor Genetics	RCV000169262	SCV004197795	pathogenic	Glycogen storage disease, type II	2023-07-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169262	SCV001459743	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing