rs543300039

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePS3PP3PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.925G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 309 (p.Gly309Arg). In a cohort of 54 Dutch patients with Pompe disease, the allele frequency of the variant was 5.5%, and evidence suggests that it is a founder variant in that population (PMID 9660056). This variant has been reported in more than 13 individuals diagnosed with Pompe disease; for at least 6 individuals, residual GAA activity is available and is in the deficient range (PMIDs 9660056, 16838077, 23430847, 23601496, 24495340, 27189384), with some patients also reported to be on enzyme replacement therapy and/or to have documentation of symptoms consistent with infantile onset Pompe disease (PMID 23402890, 23430847, 23601496, 24495340) (PP4_Moderate). More data is available in the literature but the maximum strength of evidence for PP4, as specified by the ClinGen LSD VCEP, can already be applied.. Ten of these individuals are compound heterozygous for the variant and a pathogenic variant (PMID:9660056, 16838077, 16917947, 23402890, 23430847), phase unknown in all cases, and one is homozygous (PMID:23601496)(PM3_Very strong). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In functional studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.963, 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: 188797; 2 star review status) with 8 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved on August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA273972/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 7.93

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 10 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.925G>A	p.Gly309Arg	missense_variant	Exon 5 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.925G>A	p.Gly309Arg	missense_variant	Exon 5 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152212

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000286

AC:

AN:

244726

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000454

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1459274

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

725920

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.0000384

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74482

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000505

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:11

Apr 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAA c.925G>A; p.Gly309Arg variant (rs543300039) is reported homozygous and compound heterozygous in the literature in multiple individuals affected with Pompe disease (Aminoso 2022, Katona 2014, Kroos 1998, Thomas 2021). This variant is also reported in ClinVar (Variation ID: 188797) and is found in the general population with an overall allele frequency of 0.003% (7/244,726 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show evidence of abnormal processing (Kroos 1998). Computational analyses predict that this variant is deleterious (REVEL: 0.963). Based on available information, this variant is considered to be pathogenic. References: Aminoso C et al. Genetic analysis of 76 Spanish Pompe disease patients: Identification of 12 novel pathogenic GAA variants and functional characterization of splicing variants. Gene. 2022 Jan 15;808:145967. PMID: 34530085. Katona I, Weis J, Hanisch F. Glycogenosome accumulation in the arrector pili muscle in Pompe disease. Orphanet J Rare Dis. 2014 Feb 5;9:17. PMID: 24495340. Kroos MA et al. Glycogen storage disease type II: identification of a dinucleotide deletion and a common missense mutation in the lysosomal alpha-glucosidase gene. Clin Genet. 1998 May;53(5):379-82. PMID: 9660056. Thomas DC et al. Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease. Clin Biochem. 2021 Mar;89:14-37. PMID: 33301762. -

Sep 07, 2021

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.925G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 309 (p.Gly309Arg). In a cohort of 54 Dutch patients with Pompe disease, the allele frequency of the variant was 5.5%, and evidence suggests that it is a founder variant in that population (PMID 9660056). This variant has been reported in more than 13 individuals diagnosed with Pompe disease; for at least 6 individuals, residual GAA activity is available and is in the deficient range (PMIDs 9660056, 16838077, 23430847, 23601496, 24495340, 27189384), with some patients also reported to be on enzyme replacement therapy and/or to have documentation of symptoms consistent with infantile onset Pompe disease (PMID 23402890, 23430847, 23601496, 24495340) (PP4_Moderate). More data is available in the literature but the maximum strength of evidence for PP4, as specified by the ClinGen LSD VCEP, can already be applied.. Ten of these individuals are compound heterozygous for the variant and a pathogenic variant (PMID: 9660056, 16838077, 16917947, 23402890, 23430847), phase unknown in all cases, and one is homozygous (PMID: 23601496)(PM3_Very strong). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In functional studies, when expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.963, 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: 188797; 2 star review status) with 8 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved on August 17, 2021) -

Mar 09, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

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.Gly309Arg variant in GAA has been reported in at least 20 individuals (including 8 Dutch, 1 French, 1 Croatian, 1 Hispanic, 1 Greek) with Glycogen Storage Disease II, and segregated with disease in at least 4 affected relatives from 2 families (PMID: 9660056, 23430847, 27189384, 17616415, 23402890, 16917947, 24495340, 23601496, 16838077, 24245577; DOI: 10.21767/2380-7245.100010). This variant has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 188797). This variant has been identified in 0.010% (1/9898) of Ashkenazi Jewish chromosomes, (5/110036) of 0.004% European (non-Finnish) chromosomes, and 0.003% (1/30458) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs543300039). 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 and pulse-chase analysis provide evidence that the p.Gly309Arg variant impacts GAA activity (PMID: 9660056). 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 a pathogenic variant and in homozygosity in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly309Arg variant is pathogenic (PMID: 24495340, 23601496, 16838077). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with low GAA activity in leukocytes (PMID: 23430847, 23601496, 24495340, 17616415, DOI: 10.21767/2380-7245.100010). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a reported pathogenic variant in individuals with Glycogen Storage Disease II and other findings from the literature. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4, PS3 (Richards 2015). -

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 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.925G>A (p.Gly309Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of 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 4.6e-05 in 108582 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.925G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 309 of the GAA protein (p.Gly309Arg). This variant is present in population databases (rs543300039, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 9660056, 16917947, 17210890, 17616415, 23601496, 24245577, 24495340, 29122469). ClinVar contains an entry for this variant (Variation ID: 188797). 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: 9660056). For these reasons, this variant has been classified as Pathogenic. -

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly309Arg variant in GAA has been reported in the homozygous or compound heterozygous state in >10 individuals with Pompe disease (Kroos 1998, Kroos 2006, Montalvo 2006, Elder 2013, Hansel 2018). It has also been identified in 0.01% (1/9898) of Ashkenazi Jewish and 0.005% (5/110036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported as Pathogenic and Likely Pathogenic in ClinVar (Variation ID 188797). Computational prediction tools and conservation analysis are consistent with pathogenicity. Additionally, an in vitro functional study supports an impact on protein function (Kroos 1998). In summary, the p.Gly309Arg variant meets criteria to be classified as pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2013

Arcensus

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate significantly reduced enzyme activity (Dupe et al., 2022; Goomber et al., 2022); Not observed at 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, 33301762, 29653542, 30737479, 31086307, 32959227, 16838077, 9660056, 32071926, 16917947, 23402890, 34530085, 30367637, 24337590, 23601496, 31392188, 35302691, 36246652) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2017

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

0.96

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;H

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.91

Loss of catalytic residue at V310 (P = 0.0242);Loss of catalytic residue at V310 (P = 0.0242);

MVP

1.0

MPC

0.59

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.99

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