chr17-80110050-G-A

Variant names:

• chr17-80110050-G-A
• rs778068209
• NM_000152.5:c.1432G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3_Moderate PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1432G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 478 (p.Gly478Arg). At least seven probands with symptoms consistent with infantile-onset-Pompe disease or late-onset Pompe disease with documented deficiency of GAA activity have been reported with this variant (PMIDs 25998610, 25213570, 17616415, 28394184) (PP4_Moderate). Six of these probands are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; the variants were confirmed in trans by parental testing for one of the patients (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1,1 is 0.00002895 (Latino) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_supporting, meeting this criterion. Expression of the variant in COS7 cells resulted in <2% GAA activity in cells, indicating that this variant may impact protein function (PMID 22253258, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551295, 2 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 2 submitters classfying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM3_Strong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815317/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.34
• Publications: 14 publications found

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]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1432G>A	p.Gly478Arg	missense_variant	Exon 9 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1432G>A	p.Gly478Arg	missense_variant	Exon 9 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248486 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.85e-7 AC: 1 AN: 1460582 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726636

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111572

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 34

Alfa AF: 0.000145 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Mar 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1432G>A (p.Gly478Arg) 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 4e-06 in 248486 control chromosomes. c.1432G>A has been reported in the presumed compound heterozygous state in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Chen_2017, Hermans_2004, Lee_2014, Li_2023). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in vitro (example, Hermans_2004). The following publications have been ascertained in the context of this evaluation (PMID: 28394184, 17616415, 25998610, 14695532, 25213570, 38162137). ClinVar contains an entry for this variant (Variation ID: 551295). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly478Arg variant in GAA has been reported in seven individuals with glycogen storage disease II (PMID: 28394184, 25213570, 25998610, 17616415, 14695532) and has also been reported as likely pathogenic by Counsyl in ClinVar (VariationID: 551295). This variant has been identified in 0.003% (1/34538) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778068209). 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 using COS cells transfected with the variant provide some evidence that the p.Gly478Arg variant may impact protein function (PMID: 14695532, 19862843). 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. Additionally, this variant was reported in combination with reported pathogenic variants in individuals with glycogen storage disease II (VariationID: 4027, 194154, 403712; PMID: 25998610, 17616415, 28394184, 25213570). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4 (Richards 2015). -

Aug 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 28592009). 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. ClinVar contains an entry for this variant (Variation ID: 551295). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 17616415, 25213570, 25998610, 28394184, 28592009). This variant is present in population databases (rs778068209, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the GAA protein (p.Gly478Arg). -

Nov 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1432G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 478 (p.Gly478Arg). At least seven probands with symptoms consistent with infantile-onset-Pompe disease or late-onset Pompe disease with documented deficiency of GAA activity have been reported with this variant (PMIDs 25998610, 25213570, 17616415, 28394184) (PP4_Moderate). Six of these probands are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; the variants were confirmed in trans by parental testing for one of the patients (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1,1 is 0.00002895 (Latino) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_supporting, meeting this criterion. Expression of the variant in COS7 cells resulted in <2% GAA activity in cells, indicating that this variant may impact protein function (PMID 22253258, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551295, 2 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 2 submitters classfying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM3_Strong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		9.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.94		Loss of ubiquitination at K479 (P = 0.059);Loss of ubiquitination at K479 (P = 0.059);
MVP		1.0
MPC		0.59
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs778068209; hg19: chr17-78083849;