Submissions for variant NM_000152.5(GAA):c.1935C>A (p.Asp645Glu)

gnomAD frequency: 0.00004  dbSNP: rs28940868

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000055768	SCV002032138	pathogenic	Glycogen storage disease, type II	2021-09-07	reviewed by expert panel	curation	The NM_000152.5:c.1935C>A variant in GAA is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 645 (p.Asp645Glu). At least 50 individuals with this variant have been reported with GAA activity in the affected range for Pompe disease in fibroblasts, lymphocytes, or dried blood spots (PMID: 8094613, 9554747, 18458862). This variant is reported to be the most common variant identified in patients with infantile onset Pompe disease from China, Taiwan, and Thailand (PMID 9554747, 18458862, 21039225, 31342611), although it has also been reported in other populations (PMID: 8094613). It has been found to be associated with a specific haplotype, which includes the pseudodeficiency variant, indicating that it is a founder variant (PMID: 9554747). However, other studies have not found an association with this specific haplotype (PMID: 8094613, 18458862) (PP4_Moderate). This variant was found in compound heterozygosity with a pathogenic variant in 5 patients (PMID: 8094613, 9554747, 18458862, 28394184), as well as over 30 homozygotes (PMID: 9554747, 18458862, 28394184). More data is available in the literature but the maximum amount of evidence required for PM3_Strong has been reached. The highest population minor allele frequency in gnomAD is 0.001729 in the East Asian population. This is higher than the ClinGen LSD VCEP threshold (<0.001) for PM2, and therefore does not meet this criterion. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Measurement of GAA activity in COS cells transfected with the variant showed <10% normal GAA activity indicating that this variant impacts protein function (PMID: 8094613, 19862843). In addition, little to no mature 76 kDa protein was detected by pulse-chase analysis, suggesting abnormal synthesis and/or processing of the protein (PMID: 8094613) (PS3_Moderate). Another missense variant, c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Storage Disorders VCEP (PM5). There is a ClinVar entry for this variant (Variation ID 4029; 2 star review status) with seven laboratory 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 met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PM5, PS3_Moderate, PP4_Moderate, PP3. (Classification approved on August 17, 2021)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000055768	SCV000752045	pathogenic	Glycogen storage disease, type II	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 645 of the GAA protein (p.Asp645Glu). This variant is present in population databases (rs28940868, gnomAD 0.2%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of China, Taiwan and Thailand ancestry (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). ClinVar contains an entry for this variant (Variation ID: 4029). 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: 8094613). This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 15145338, 17723315, 20830524). 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.
Baylor Genetics	RCV000055768	SCV000807221	pathogenic	Glycogen storage disease, type II	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055768	SCV000919370	pathogenic	Glycogen storage disease, type II	2018-02-08	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1935C>A (p.Asp645Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 269490 control chromosomes. c.1935C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. This variant has been reported to be one of the most common mutations among Chinese patients with Pompe disease, suggesing a founder effect. At least one publication reports experimental evidence evaluating an impact on protein function resulting in 10%-<30% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000055768	SCV001190560	pathogenic	Glycogen storage disease, type II	2019-05-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000055768	SCV001193876	pathogenic	Glycogen storage disease, type II	2019-12-20	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1935C>A(D645E) is classified as pathogenic in the context of Pompe disease and is associated with the infantile-onset form of this disease. Sources cited for classification include the following: PMID 8094613, 21232767, 16702877, 21039225 and 10338092. Classification of NM_000152.3(GAA):c.1935C>A(D645E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000055768	SCV001422758	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Asp645Glu variant in GAA has been reported in at least 48 individuals (including 42 individuals from China or Taiwan and 5 individuals from Thailand) with Glycogen Storage Disease II (PMID: 8094613, 21039225, 21232767, 10338092, 9554747), and has also been reported pathogenic by Counsyl, Invitae, Baylor Genetics, OMIM, and GeneReviews in ClinVar (Variation ID: 4029). This variant has been identified in 0.173% (34/19660) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28940868). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Asp645Glu variant may impact protein function (PMID: 8094613, 8935410). 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 with reported pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp645Glu variant is pathogenic (PMID: 9554747, 8094613). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in fibroblasts, consistent with disease (PMID: 9554747, 8094613). Three additional variants at the same position, (p.Asp645Asn, p.Asp645His, and p.Asp645Tyr), have been reported pathogenic or likely pathogenic in association with Glycogen Storage Disease II in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 188728, 556386, 189013). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II, multiple pathogenic or likely pathogenic variants reported at the same position, and in vitro functional studies with COS cells transfected with this variant. ACMG/AMP Criteria applied: PM3_Strong, PM5_Strong, PS3, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV001785448	SCV002021200	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018551	SCV004875747	pathogenic	Cardiovascular phenotype	2023-10-03	criteria provided, single submitter	clinical testing	The c.1935C>A (p.D645E) alteration is located in exon 14 (coding exon 13) of the GAA gene. This alteration results from a C to A substitution at nucleotide position 1935, causing the aspartic acid (D) at amino acid position 645 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.012% (34/274238) total alleles studied. The highest observed frequency was 0.173% (34/19660) of East Asian alleles. This variant has been detected as homozygous in multiple individuals and in conjunction with a second GAA variant in multiple individuals diagnosed with glycogen storage disease II; however, the phase of the two variants was not specified (Ko, 1999; Chan, 2023). Three other alterations at the same codon, c.1933G>A (p.D645N), c.1933G>C (p.D645H), and c.1933G>T(p.D645Y), have been reported (Lin, 1995; Huie, 1998; Gort, 2007). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001785448	SCV005325580	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 8094613); 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: 33301762, 30275481, 31086307, 32711049, 32014045, 32005694, 22975760, 21232767, 21439876, 21228398, 8935410, 9554747, 28394184, 1684505, 16702877, 31953985, 32411386, 35314707, 8094613, 20080426, 9535769, 27344650)
OMIM	RCV000004244	SCV000024410	pathogenic	Glycogen storage disease type II, infantile	1998-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000055768	SCV000086726	not provided	Glycogen storage disease, type II		no assertion provided	literature only
Natera, Inc.	RCV000055768	SCV001459742	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751197	SCV005365208	pathogenic	GAA-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The GAA c.1935C>A variant is predicted to result in the amino acid substitution p.Asp645Glu. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with glycogen storage disease (see for example, Table 2, Chien et al. 2011. PubMed ID: 21232767; Table 1, Chen et al. 2017. PubMed ID: 28394184; Table 1, Chan et al. 2023. PubMed ID: 37542277). This variant is reported in 0.17% of alleles in individuals of East Asian descent in gnomAD. In vitro experimental studies suggest this variant reduces protein activity (Table 2, Hermans et al. 1993. PubMed ID: 8094613; Table 1, Chan et al. 2023. PubMed ID: 37542277). Alternate nucleotide substitutions affecting the same amino acid (p.Asp645Asn and p.Asp645His) have been reported in the homozygous and compound heterozygous states in multiple individuals with glycogen storage disease (see for example, Table S3, Kishnani et al. 2019. PubMed ID: 31086307; Table 1, Thomas et al. 2020. PubMed ID: 33301762; Table 3, Li et al. 2023. PubMed ID: 38162137). In summary, the c.1935C>A (p.Asp645Glu) variant is interpreted as pathogenic.