chr17-80110950-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PM2_SupportingPS3_ModeratePM3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1561G>A variant in GAA is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 521 (p.Glu521Lys). This substitution of a negatively charged, polar amino acid with a neutral, non-polar amino acid is predicted to functionally impact the GAA precursor protein (PMID:1898413). This variant was first reported in homozygosity in a case report of siblings with IOPD and no detectable GAA activity in fibroblasts (PMID:1898413), meeting criteria for PP4_moderate. This variant has been detected in at least four additional individuals with IOPD. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMIDs: 17723315, 37542277) and two were homozygous for the variant (PMIDs: 19862843,33301762). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517,34852371 and 39045638), and one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID:21605996 and 22676651) (PM3_Very Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003334 (2/59992 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In the first report of this variant, transient expression in COS cells was performed and revealed no detectable activity, and immunocytochemistry results suggested the mutant precursor is not transported to the lysosome (PMID:1898413). Subsequent expression studies in COS cells revealed <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843). Thus, PS3_Supporting can be applied. The computational predictor REVEL gives a score of 0.932 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position (p.Glu521Gln) has been reported in IOPD (PMID:22658377, 19588081), but this variant has not been reviewed by the ClinGen Lysosomal Diseases Variant Curation Expert panel and thus PM5 will not be applied. There is a ClinVar entry for this variant (Variation ID: 4022, 2-star review status) with 8 submitters classifying the variant as pathogenic (7 submitters) or likely pathogenic (1 submitters). 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_Very Strong, PP4_moderate, PM2_supporting, PP3, PS3_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 3, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116593/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 9.80

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 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 link	c.1561G>A	p.Glu521Lys	missense_variant	Exon 11 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.1561G>A	p.Glu521Lys	missense_variant	Exon 11 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251268

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135856

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:8

Aug 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 521 of the GAA protein (p.Glu521Lys). This variant is present in population databases (rs121907937, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Pompe disease (PMID: 1898413, 17723315). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4022). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 1898413). For these reasons, this variant has been classified as Pathogenic. -

Nov 20, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 03, 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.1561G>A variant in GAA is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 521 (p.Glu521Lys). This substitution of a negatively charged, polar amino acid with a neutral, non-polar amino acid is predicted to functionally impact the GAA precursor protein (PMID: 1898413). This variant was first reported in homozygosity in a case report of siblings with IOPD and no detectable GAA activity in fibroblasts (PMID: 1898413), meeting criteria for PP4_moderate. This variant has been detected in at least four additional individuals with IOPD. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMIDs: 17723315, 37542277) and two were homozygous for the variant (PMIDs: 19862843,33301762). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517,34852371 and 39045638), and one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID:21605996 and 22676651) (PM3_Very Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003334 (2/59992 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In the first report of this variant, transient expression in COS cells was performed and revealed no detectable activity, and immunocytochemistry results suggested the mutant precursor is not transported to the lysosome (PMID: 1898413). Subsequent expression studies in COS cells revealed <2% wild type GAA activity, indicating that this variant may impact protein function (PMID: 19862843). Thus, PS3_Supporting can be applied. The computational predictor REVEL gives a score of 0.932 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position (p.Glu521Gln) has been reported in IOPD (PMID: 22658377, 19588081), but this variant has not been reviewed by the ClinGen Lysosomal Diseases Variant Curation Expert panel and thus PM5 will not be applied. There is a ClinVar entry for this variant (Variation ID: 4022, 2-star review status) with 8 submitters classifying the variant as pathogenic (7 submitters) or likely pathogenic (1 submitters). 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_Very Strong, PP4_moderate, PM2_supporting, PP3, PS3_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 3, 2024) -

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Glu521Lys variant in GAA has been reported in 11 individuals (including at least 3 Caucasian and 2 Indian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 21605996, 19862843, 22704482, 1898413, 17723315, 17027861, 22676651, 25673129, 20033296, 20308911), and has been identified in 0.003% (1/30616) of South Asian chromosomes by gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907937). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported likely pathogenic by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4022). Another variant at this position, p.Glu521Val, has been reported as a VUS in association with disease in the literature (PMID: 25526786). In vitro functional studies, including transfection of COS cells and a Western Blot, provide some evidence that the p.Glu521Lys variant may impact protein processing and function (PMID: 1898413, 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. The presence of this variant in combination with reported pathogenic variants in compound heterozygous individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu521Lys variant is pathogenic (PMID: 25673129, 17723315, 20033296). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on GAA enzyme activity assays (PMID: 21605996, 25673129, 22676651, 20033296, 17723315, 1898413). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015). -

May 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is in trans with NM_000152.5:c.1556T>C variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004022). The variant is in trans with the other variant. Different missense changes at the same codon (p.Glu521Gln, p.Glu521Val) have been reported to be associated with GAA related disorder (ClinVar ID: VCV000972760 / PMID: 18425781, 25526786). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

May 23, 2022

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.1561G>A (p.Glu521Lys) results in a conservative amino acid change in the encoded protein sequence. Four 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 251268 control chromosomes. c.1561G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in the homozygous and compound heterozygous state (eg. Hermans_1991, Herzog_2012, Liu_2014, Montagnese_2016, etc). These data indicate that the variant is very likely to be associated with disease. The variant has been reported to have <10% enzyme activity in cell culture experiments (Hermans_1991, Flanagan_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAA: PM3:Strong, PM1, PM2, PM5, PP3 -

Feb 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease type II, infantile

Pathogenic:1

Sep 16, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MVP

1.0

MPC

0.57

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over