Submissions for variant NM_000152.5(GAA):c.1912G>T (p.Gly638Trp)

gnomAD frequency: 0.00002  dbSNP: rs757617999

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001243631	SCV005089707	pathogenic	Glycogen storage disease, type II	2024-06-06	reviewed by expert panel	curation	The NM_000152.5:c.1912G>T variant in GAA is predicted to result in the substitution of glycine by tryptophan at amino acid 638, (p.Gly638Trp). At least 14 individuals diagnosed with Pompe disease have been reported with this variant. Of those individuals, two have symptoms reported to be consistent with infantile onset Pompe disease (including cardiac symptoms and hypotonia) and are on enzyme replacement therapy (PMIDs:19588081, 28763149, 31086307), and two patients with late onset Pompe disease are reported with laboratory values showing reduced GAA activity (PMIDs: 36299500) and two of them are also treated with ERT (PMIDs: 24923245, 17573812, 17643989, 21484825, 25455803, 27189384) (PP4_Moderate). Ten individuals are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The second variant includes c.-32-13T>G (ClinVar Variation ID: 4027) (7 individuals, all phase unknown; max 1 point counted) (PMIDs: 10737124, 24923245, 28763149, 29181627, 30564623, 36299500); c.2481+102_2646+31del, phase unknown, 0.5 points (PMID: 29122469), and c.2608C>T (p.Arg870Ter) (ClinVar Variation ID: 189009, SCV001371741.1) (confirmed in trans, 1 point) (PMID: 28763149, 31086307) (ClinVar Variation ID: 189009, SCV001371741.1), and c.1913G>T (p.Gly638Val) (confirmed in trans, 1 point) (PMID: 19588081). At least one individual is homozygous for the variant (PMIDs: 18429042, 31086307). Total 4 points (PM3_VeryStrong). In addition, three individuals are compound heterozygous for the variant and either c.1829C>T (p.Ala610Val) (PMID: 17573812, 17643989, 21484825, 25455803, 27189384), c.2294G>A (p.Gly765Asp) (PMID: 24627108), c.2294G>A (p.Gly765Asp) (PMID: 31086307). The allelic data for these individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency (MAF) in gnomAD v2.1.1. is 0.00006752 (1/14810 alleles) in the African/African-American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In gnomAD v4.1. the highest MAF is 0.00001335 (1/74902 alleles) in the African/African-American population, also meeting PM2_Supporting. When expressed in COS-7 cells, the variant resulted in <2% control activity (PMID: 19862843). The computational predictor REVEL gives a score of 0.988 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another amino acid change at the same position, c.1913G>T (p.Gly638Val), has been reported in patients with Pompe disease. This data was used in the assessment of p.Gly638Val and is not included here to avoid circular logic.. There is a ClinVar entry for this variant (ClinVar Variation ID: 280954) 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 (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)
Eurofins Ntd Llc (ga)	RCV000333327	SCV000330939	pathogenic	not provided	2016-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243631	SCV001416800	pathogenic	Glycogen storage disease, type II	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 638 of the GAA protein (p.Gly638Trp). This variant is present in population databases (rs757617999, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 10737124, 17573812, 18429042, 19588081, 28763149, 29122469, 29181627). 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: 280954). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 19862843). This variant disrupts the p.Gly638 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15121988, 19588081). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001243631	SCV001423070	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly638Trp variant in GAA has been reported in 7 individuals (including 2 Spanish, 2 German, 1 Italian, and 1 Brazilian individuals) with Glycogen Storage Disease II (PMID: 17616415, 18429042, 21484825, 17573812, 19588081, 10737124), and has also been reported pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 280954). This variant has been identified in 0.007% (1/14810) of African chromosomes, 0.003% (1/29634) of South Asian chromosomes, and 0.001% (1/109192) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757617999). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissues (PMID: 17616415, 17573812, 28763149). The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly638Trp variant is pathogenic (PMID: 17616415, 17573812, 28763149). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001243631	SCV001983407	pathogenic	Glycogen storage disease, type II	2021-09-10	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1912G>T (p.Gly638Trp) 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 1.2e-05 in 242160 control chromosomes. c.1912G>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Gort_2007, Kishnani_2019). These data indicate that the variant is very likely to be associated with disease. Three 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000333327	SCV002025211	pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000333327	SCV002065839	pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing	The c.1912G>T variant in exon 14 results in an amino acid change, p.Gly638Trp. This sequence change has been reported in the homozygous and compound heterozygous state in multiple individuals with GAA-related disorders (PMID: 18429042, 31342611, 10737124, 31086307, 29181627). Other nucleotide changes resulting in a different amino acid change at the same residue have been reported in individuals with glycogen storage disease type 2 indicating that this residue is important to the GAA protein (PMID: 32888769, 31086307). This sequence change has been described in the gnomAD database in three individuals with an overall population frequency of 0.0012% (dbSNP rsrs757617999). The p.Gly638Trp change affects a highly conserved amino acid residue located in a domain of the GAA protein that is known to be functional. The p.Gly638Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Additionally, this variant has been reported to impact the function of the GAA protein (PMID: 19862843). Splicing prediction algorithms indicate this sequence change may impact splicing although functional studies have not been performed to confirm this. Based on these evidences, the c.1912G>T variant is classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000333327	SCV002501206	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001243631	SCV004195511	pathogenic	Glycogen storage disease, type II	2023-08-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000333327	SCV005396374	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 19862843); 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; This variant is associated with the following publications: (PMID: 32849613, 24627108, 34885805, 31342611, 35109913, 27189384, 19862843, 34501319, 29122469, 31086307, 29181627, 31254424, 30564623, 10737124, 22834902)
Fulgent Genetics, Fulgent Genetics	RCV001243631	SCV005653225	pathogenic	Glycogen storage disease, type II	2024-05-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001243631	SCV002092079	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing