rs7215458

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg).The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID:29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID:37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815294/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:8

Conservation

PhyloP100: 3.66

Publications

6 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_benign. The variant received -5 ACMG points.

BP4

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

BS1

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.1352C>G	p.Pro451Arg	missense_variant	Exon 9 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.1352C>G	p.Pro451Arg	missense_variant	Exon 9 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

197

AN:

152278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00446

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000380

AC:

AN:

250328

AF XY:

0.000214

show subpopulations

Gnomad AFR exome

AF:

0.00441

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

307

AN:

1460998

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.00523

AC:

175

AN:

33476

American (AMR)

AF:

0.000380

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52690

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

1111906

Other (OTH)

AF:

0.000613

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00131

AC:

200

AN:

152396

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00452

AC:

188

AN:

41604

American (AMR)

AF:

0.000327

AC:

AN:

15312

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:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68042

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000753

Hom.:

Bravo

AF:

0.00154

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000437

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:5

Feb 26, 2021

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 20, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg). The highest population minor allele frequency in gnomAD v4.1.0 is 0.004835 (363/75080) alleles, including 4 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID: 29149851). The variant was also reported in a patient with autism spectrum disorder but no reported diagnosis of Pompe disease (PMID: 37492102). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert panel on May 20, 2025) -

Dec 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Aug 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P451R variant (also known as c.1352C>G), located in coding exon 8 of the GAA gene, results from a C to G substitution at nucleotide position 1352. The proline at codon 451 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a limb girdle muscular dystrophy cohort and an autism spectrum disorder cohort (Johnson K et al. Orphanet J Rare Dis, 2017 Nov;12:173; Tuncay IO et al. Cell Genom, 2023 Jul;3:100322). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Benign:1

Jan 13, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GAA-related disorder

Benign:1

Feb 07, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Feb 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Benign

0.18

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.85

.;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.021

T;T

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

3.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.45

Sift

Benign

0.070

T;T

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.96

D;D

Vest4

0.52

MVP

1.0

MPC

0.49

ClinPred

0.042

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.74

Mutation Taster

=99/1

polymorphism

(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