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.1832G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartate at amino acid 611 (p.Gly611Asp). Four patients with a diagnosis of Pompe disease and this variant have been reported including two with documented features of infantile onset Pompe disease and laboratory values showing deficient GAA activity <1% in skin fibroblasts (PMID:22252923) or in the affected range in dried blood spot assay (PMID:25681614), and another reported with features consistent with infantile onset Pompe disease and deficient GAA activity but the laboratory value was not provided (PMID:24269976). Finally, a patient with deficient GAA activity (level not known) was identified in clinical laboratory data (PP4_Moderate). Of the reported patients, three are compound heterozygous for the variant and a variant classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP including c.2501_2502delCA, (pathogenic, presumed in trans, clinical laboratory data), c.1848dupC (clinical laboratory data) (pathogenic, phase unknown), and c.1843G>A (p.Gly615Arg) (PMID:24269976) (likely pathogenic, phase unknown), and one patient is homozygous (PMID:25681614). Another patient is compound heterozygous for the variant and c.1570A>T (p.Asn524Tyr). However, the allelic data from this patient with be used in the assessment of p.Asn524Tyr and is not included here to avoid circular logic. (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.821 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.1831G>A, p.Gly611Ser) (ClinVar variation ID: 935199) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP. However, the data from c.1832 (p.Gly611Asp) was used in the classification of p.Gly611Ser, and therefore the data is not ncluded here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 371226, 1 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 1 submitter classifying the variant as a Variant of Uncertain Significance. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041897/MONDO:0009290/010

Frequency

Genomes: not found (cov: 33)

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 4.52

Publications

9 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:

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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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	NM_000152.5	MANE Select	c.1832G>A	p.Gly611Asp	missense	Exon 13 of 20	NP_000143.2
GAA	NM_001079803.3		c.1832G>A	p.Gly611Asp	missense	Exon 14 of 21	NP_001073271.1
GAA	NM_001079804.3		c.1832G>A	p.Gly611Asp	missense	Exon 13 of 20	NP_001073272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	ENST00000302262.8	TSL:1 MANE Select	c.1832G>A	p.Gly611Asp	missense	Exon 13 of 20	ENSP00000305692.3
GAA	ENST00000390015.7	TSL:1	c.1832G>A	p.Gly611Asp	missense	Exon 14 of 21	ENSP00000374665.3
GAA	ENST00000570803.6	TSL:5	c.1832G>A	p.Gly611Asp	missense	Exon 13 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

245780

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

PhyloP100

4.5

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MutPred

0.87

Loss of MoRF binding (P = 0.0638)

MVP

1.0

MPC

0.62

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Mutation Taster

=14/86

disease causing (ClinVar)

(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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rs1057517105

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over