rs398123169

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_ModeratePP3PM2_SupportingPM3PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1465G>A variant in GAA is a missense variant that is predicted to result in the substitution of aspartate by asparagine at amino acid 489 (p.Asp489Asn). This variant has been detected in at least 10 patients reported to have Pompe disease including 7 individuals with reported laboratory values demonstrating deficient GAA activity (PMID:17151339, 22081099, 22658377, 24395639, 24844452, 24923245, 29422078, 31193175), and three for whom GAA activity was not reported but who were treated by enzyme replacement (PMIDs: 25626711, 28574618). Nine individuals were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 16917947, 2208109, 24395639, 24844452, 24923245, 28574618), c.40_47del8 (PMID:29422078), c.307T>G (p.Cys103Gly) (PMID:18429042), c.1799G>A (p.Arg600His) (PMID:22711147), c.2014C>T (p.Arg672Trp) (PMID:16917947, 2208109), and another individual was compound heterozygous for the variant and c.2481+110_2646+39del (labeled as c.IVS17 + 102_IVS18 + 31 in the paper) confirmed in trans (PMID:25626711). The variant was also detected in a parent of two affected children, now deceased, with c.1962_1964delAGA (p.Glu655del) in the other parent. However, as these variants were not confirmed to be present in the affected children, the data is not included (PMID:22711147). Another individual was reported to have the variant but the cDNA sequence was not provided (PMID:17616415 (PM3_VeryStrong). The highest population minor allele frequency in gnomAD is 0.00005 (1/21638) in the European Finnish population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In two different studies, this variant results in <2% GAA activity when expressed in COS-7 cells or Ad5-SV40 immortalized human GAA-deficient fibroblasts and, on Western blot, most of the gene product remained as the 110 kDa inactive precursor (PMID:17915575, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.938 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: 92465). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP, February 7, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220390/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.40

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.1465G>A	p.Asp489Asn	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.1465G>A	p.Asp489Asn	missense_variant	Exon 10 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251130

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135846

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:

0.0000462

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

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:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:7

Nov 03, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 489 of the GAA protein (p.Asp489Asn). This variant is present in population databases (rs398123169, gnomAD 0.004%). This missense change has been observed in individual(s) with glycogen storage disease type II (GSDII) (PMID: 16917947, 24844452, 29422078). 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: 92465). 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: 16917947). For these reasons, this variant has been classified as Pathogenic. -

Feb 07, 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.1465G>A variant in GAA is a missense variant that is predicted to result in the substitution of aspartate by asparagine at amino acid 489 (p.Asp489Asn). This variant has been detected in at least 10 patients reported to have Pompe disease including 7 individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 17151339, 22081099, 22658377, 24395639, 24844452, 24923245, 29422078, 31193175), and three for whom GAA activity was not reported but who were treated by enzyme replacement (PMIDs: 25626711, 28574618). Nine individuals were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 16917947, 2208109, 24395639, 24844452, 24923245, 28574618), c.40_47del8 (PMID: 29422078), c.307T>G (p.Cys103Gly) (PMID: 18429042), c.1799G>A (p.Arg600His) (PMID: 22711147), c.2014C>T (p.Arg672Trp) (PMID: 16917947, 2208109), and another individual was compound heterozygous for the variant and c.2481+110_2646+39del (labeled as c.IVS17 + 102_IVS18 + 31 in the paper) confirmed in trans (PMID: 25626711). The variant was also detected in a parent of two affected children, now deceased, with c.1962_1964delAGA (p.Glu655del) in the other parent. However, as these variants were not confirmed to be present in the affected children, the data is not included (PMID: 22711147). Another individual was reported to have the variant but the cDNA sequence was not provided (PMID: 17616415 (PM3_VeryStrong). The highest population minor allele frequency in gnomAD is 0.00005 (1/21638) in the European Finnish population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In two different studies, this variant results in <2% GAA activity when expressed in COS-7 cells or Ad5-SV40 immortalized human GAA-deficient fibroblasts and, on Western blot, most of the gene product remained as the 110 kDa inactive precursor (PMID: 17915575, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.938 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: 92465). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PM3_VeryStrong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023). -

Mar 25, 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.Asp489Asn variant in GAA has been reported in 15 individuals (including 9 Italian, 1 Spanish, and 1 French individuals) with Glycogen Storage Disease II (PMID: 22081099, 17616415, 18429042, 22711147, 22658377, 24844452, 22980766, 25103075; DOI: 10.12032/TMRTH201804005), and has also been reported likely pathogenic by Counsyl and Fulgent Genetics and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 92465). This variant has been identified in 0.004621% (1/21638) of European (Finnish) chromosomes, 0.003% (1/30614) of South Asian chromosomes, and 0.001% (1/113488) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123169). 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 with COS cells transfected with this variant provide some evidence that the p.Asp489Asn variant may impact GAA activity (PMID: 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 pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp489Asn variant is pathogenic (PMID: 22658377, 22081099; 10.12032/TMRTH201804005). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected by assays with relevant tissue (PMID: 17151339, 22658377, 22081099, 17616415; DOI: 10.12032/TMRTH201804005). 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 with COS cells transfected with this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015). -

Apr 19, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.1465G>A (p.Asp489Asn) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120924 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple affected individuals and GAA activity testing confirm the variant results in deficiency. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:3

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.98

Loss of glycosylation at T494 (P = 0.2356);Loss of glycosylation at T494 (P = 0.2356);

MVP

1.0

MPC

0.54

ClinPred

1.0

GERP RS

5.5

Varity_R

0.96

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 19

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