rs786204622

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM2_SupportingPM3_StrongPS3_SupportingPM1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID:14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID:31086307), and c.2481+102_c.2646+31del (PMID:26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID:31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID:26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID:29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID:14695532, 19862843). The computational predictor REVEL gives a score of 0.967 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: ). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274247/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15

Conservation

PhyloP100: 7.52

Publications

14 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: Pathogenic. The variant received 11 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM1

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 link	c.1441T>C	p.Trp481Arg	missense_variant	Exon 10 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.1441T>C	p.Trp481Arg	missense_variant	Exon 10 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250876

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461552

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1111914

Other (OTH)

AF:

0.0000331

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

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:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000411

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:10

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 481 of the GAA protein (p.Trp481Arg). This variant is present in population databases (rs772883420, gnomAD 0.008%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18757064; internal data). 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: 189007). 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: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic. -

Oct 10, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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. -

Jun 22, 2018

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.1441T>C (p.Trp481Arg) 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 2.2e-05 in 276888 control chromosomes. c.1441T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), with reported severely deficient GAA enzyme activity (Tsai_2017, Hermans_2004, Herzog_2012, Raben_1998, van Capelle2016). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 2023

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID: 14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID: 31086307), and c.2481+102_c.2646+31del (PMID: 26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID: 31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID: 26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID: 14695532, 19862843). The computational predictor REVEL gives a score of 0.967 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: ). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023) -

Jan 22, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Trp481Arg variant in GAA has been reported in 6 individuals (including 1 African American and 1 German individuals) with Glycogen Storage Disease II (PMID: 27189384, 18757064, 10189220, 19862843, 26497565, 22676651, 14695532, 28657663), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 189007). This variant has been identified in 0.008% (2/24904) of African chromosomes and 0.003% (4/128730) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772883420). 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 provide some evidence that the p.Trp481Arg variant may impact ligand binding and GAA activity but not GAA levels (PMID: 19862843, 14695532, 15501829). 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 combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp481Arg variant is pathogenic (PMID: 26497565, 22676651, 27189384, 28657663). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on very low GAA activity in assays with relevant tissue (PMID: 26497565, 22676651, 27189384, 28657663). In summary, this variant meets criteria to be classified as pathogenic for p.Trp481Arg in an autosomal recessive manner based on in vitro functional evidence and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -

Mar 06, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2017

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GAA c.1441T>C; p.Trp481Arg variant (rs772883420) is reported in the literature in individuals with glycogen storage disease who carry an additional pathogenic GAA variant (Raben 1999, Tsai 2017, van der Meijden 2018). The p.Trp481Arg variant is also reported in ClinVar (Variation ID: 189007). It is observed in the general population with an overall allele frequency of 0.002% (6/282252 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.967). In support of these predictions, functional characterization of the variant protein shows altered function (Flanagan 2009, Hermans 2004). Based on available information, this variant is considered to be likely pathogenic. References: Flanagan JJ et al. The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase. Hum Mutat. 2009 Dec;30(12):1683-92. PMID: 19862843. Hermans MM et al. Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. Hum Mutat. 2004 Jan;23(1):47-56. PMID: 14695532. Raben N et al. Lee E, Lee L, Hirschhorn R, Plotz PH. Novel mutations in African American patients with glycogen storage disease Type II. Mutations in brief no. 209. Online. Hum Mutat. 1999;13(1):83-4. PMID: 10189220. Tsai AC et al. Next generation deep sequencing corrects diagnostic pitfalls of traditional molecular approach in a patient with prenatal onset of Pompe disease. Am J Med Genet A. 2017 Sep;173(9):2500-2504. PMID: 28657663. van der Meijden JC et al. Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy. J Inherit Metab Dis. 2018 Nov;41(6):1205-1214. PMID: 29556838. -

not provided

Pathogenic:4

Oct 12, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a 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: 31254424, 19862843, 21228398, 28657663, 22676651, 18757064, 15501829, 16580018, 31086307, 10189220, 14695532, 26497565, 27189384, 33202836, 29556838, 27535533, 22253258, 19343043) -

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3_strong, PP4_moderate, PM3_strong, PS3_supporting -

Jun 28, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jan 03, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W481R pathogenic mutation (also known as c.1441T>C), located in coding exon 9 of the GAA gene, results from a T to C substitution at nucleotide position 1441. The tryptophan at codon 481 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other GAA variant(s) in individual(s) with features consistent with glycogen storage disease type II (Raben N et al. Hum Mutat, 1999;13:83-4; Hermans MM et al. Hum Mutat, 2004 Jan;23:47-56; Flanagan JJ et al. Hum Mutat, 2009 Dec;30:1683-92; Broomfield A et al. J Inherit Metab Dis, 2016 Mar;39:261-71; Tsai AC et al. Am J Med Genet A, 2017 Sep;173:2500-2504; Desai AK et al. Mol Genet Metab Rep, 2019 Sep;20:100475; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6:[ePub ahead of print]; Viamonte MA et al. J Hum Genet, 2021 Nov;66:1089-1099; Zhang T et al. Mol Genet Metab, 2022 Aug;136:296-305). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H

PhyloP100

7.5

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-13

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.94

Gain of methylation at W481 (P = 0.0094);Gain of methylation at W481 (P = 0.0094);

MVP

1.0

MPC

0.72

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over