17-80117723-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID:33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID:22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815746/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:6

Conservation

PhyloP100: 2.30

Publications

2 publications found

Variant links:

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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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 link	c.2455C>T	p.Arg819Trp	missense_variant	Exon 17 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.2455C>T	p.Arg819Trp	missense_variant	Exon 17 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000247

AC:

AN:

243096

AF XY:

0.0000227

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000879

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1459040

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

725742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.0000898

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000349

AC:

AN:

86066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51886

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111438

Other (OTH)

AF:

0.0000332

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:3Uncertain:2

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5:c.2455C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 819 (p.Arg819Trp). Two patients with this variant have been reported, both with documented values showing reduced GAA activity, and one with confirmed absence of pseudodeficiency variants (Clinical Diagnostic Laboratory, PMID: 33741225) (PP4_Moderate). One of these patients is compound heterozygous for the variant, in trans (based on testing of one parent) with a pathogenic variant in GAA, c.-32-13T>G (Clinical Diagnostic Laboratory). The other patient is compound heterozygous for the variant and c.2189+5_2189+8delGTGA. The allelic data from this patient will be used in the classification of the intronic variant and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006687 (4/59818 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion. The computational predictor REVEL gives a score of 0.822 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant at this same amino acid position (c.2456 G>C, p.Arg819Pro) has been reported in individuals with Pompe disease (PMID: 22252923). There is a ClinVar entry for this variant (Variation ID: 456402). In summary, this variant meets the criteria to be classified as likely apthogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the Clingen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023). -

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 819 of the GAA protein (p.Arg819Trp). This variant is present in population databases (rs61736895, gnomAD 0.009%). This missense change has been observed in individual(s) with Pompe disease (PMID: 33741225). ClinVar contains an entry for this variant (Variation ID: 456402). 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%. This variant disrupts the p.Arg819 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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

Uncertain:2

Aug 22, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 19343043, 22253258, 33741225) -

Jul 31, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 03, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GAA c.2455C>T (p.Arg819Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2.5e-05 in 243096 control chromosomes. c.2455C>T has been reported in the literature in an individual affected with Glycogen Storage Disease (example: Puri_2021). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.2456G>C, p.Arg819Pro), supporting the critical relevance of codon 819 to GAA protein function. The following publication has been ascertained in the context of this evaluation (PMID: 33741225). ClinVar contains an entry for this variant (Variation ID: 456402). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cardiovascular phenotype

Uncertain:1

Jul 18, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R819W variant (also known as c.2455C>T), located in coding exon 16 of the GAA gene, results from a C to T substitution at nucleotide position 2455. The arginine at codon 819 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

4.3

H;H

PhyloP100

2.3

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.80

Loss of methylation at R819 (P = 0.0222);Loss of methylation at R819 (P = 0.0222);

MVP

1.0

MPC

0.54

ClinPred

1.0

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

Mutation Taster

=22/78

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over