rs28940868

chr17-80112922-C-Achr17-80112922-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000152.5(GAA):c.1935C>A(p.Asp645Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D645N) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 0.998

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80112920-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 188728.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 17-80112922-C-A is Pathogenic according to our data. Variant chr17-80112922-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4029.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112922-C-A is described in Lovd as [Pathogenic]. Variant chr17-80112922-C-A is described in Lovd as [Likely_pathogenic]. Variant chr17-80112922-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1935C>A	p.Asp645Glu	missense_variant	14/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1935C>A	p.Asp645Glu	missense_variant	14/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 28 AN: 242876 Hom.: 0 AF XY: 0.000106 AC XY: 14 AN XY: 132090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00155

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1458426 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 725200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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 -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 07, 2021	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) -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 1-year-old female with infantile Pompe disease -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	May 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Glycogen storage disease type II, infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 20, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H
MutationTaster	Benign	0.92	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		1.0		Loss of stability (P = 0.287);Loss of stability (P = 0.287);
MVP		1.0
MPC		0.53
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28940868; hg19: chr17-78086721;