rs753269119

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePM3_StrongPP3PM2_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1856G>A variant in GAA is a missense variant predicted to cause substitution of serine by asparagine at amino acid 619 (p.Ser619Asn). At least five probands with symptoms consistent with late-onset-Pompe disease have been reported with this variant (PMIDs 24158270, 16838077, 25052852, 37087815,22194990), two with documented deficiency of GAA activity (PMIDs 24158270, 16838077) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G (PMID:25052852). The other three patients are compound heterozygous with unknown phase for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G, c.1655T>C (p.Leu552Pro) or c.1927G>A (p.Gly643Arg), respectively (PMIDs: 37087815, 16838077, 24158270) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.0 is 0.0001875 (17/90678 alleles) in South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in <5% GAA activity in cells and <5% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 16838077 and 19862843)(PS3_Moderate). The computational predictor REVEL gives a score 0.744 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: 370146; 2-star review status) with 10 submitters classifying the variant as pathogenic, and 2 as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815500/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 7.79

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.1856G>A	p.Ser619Asn	missense_variant	Exon 13 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.1856G>A	p.Ser619Asn	missense_variant	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152036

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241268

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131764

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:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458998

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725696

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:

0.000175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:9

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.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). This variant has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370146) and has been identified in 0.013% (4/29974) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753269119). 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 provide some evidence that the p.Ser619Asn variant may impact proteolytic activation of GAA and GAA activity (PMID: 16838077, 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. One pathogenic additional variant at the the same position, p.Ser619Arg, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 550825). The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser619Asn variant is pathogenic (PMID: 16838077). Of note, this variant has also been observed in cis with the known pathogenic variant c.-32-13T>G with both variants in the homozygous state in an individual with Glycogen Storage Disorder II (PMID: 26946079). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 24158270, 26946079, 16838077). 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, another pathogenic variant at the same position, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM3_Supporting, PP4 (Richards 2015). -

Jul 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 10, 2019

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.1856G>A (p.Ser619Asn) 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 1.7e-05 in 237486 control chromosomes (gnomAD). The variant, c.1856G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2006, Remiche_2014, Gallardo_2011, Parenti_2014, Arslan_2016). One patient, Arslan_2016, was found to be homozygous for two deleterious variants, the variant of interest and c.32-13T>G, to which the authors indicate the phenotype was more progressive. The patient was born to consanguineous Turkish parents. These data indicate that the variant may 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 residual acid -glucosidase activity (Kroos_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser619Asn variant in GAA has been reported in at least 8 individuals (6 in the compound heterozygous state) with Glycogen Storage Disease II. Of note, in 2 of these individuals (one homozygote and one compound heterozygote), this variant was in cis with the known pathogenic variant c.-32-13T>G (Gallardo 2011 PMID: 22194990, Arslan 2016 PMID: 26946079, Alejaldre 2012 PMID: 22980766, Kroos 2006 PMID: 16838077, Remiche 2014 PMID: 24158270, Parenti 2014 PMID: 25052852, Fecarotta 2013 PMID: 23668440, Gutiérrez-Rivas 2015 PMID: 25998610). This variant has also been reported in ClinVar (Variation ID: 370146) and has been identified in 2/4830 of South Asian and 1/67968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using patient tissues provide some evidence that this variant may impact proteolytic activation of GAA and GAA activity (Kroos 2006 PMID: 16838077). 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. Another variant involving this codon (p.Ser619Arg) has been identified in individuals with autosomal recessive Glycogen Storage Disease II and is classified as likely pathogenic/pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM5, PP3, PM3_Very strong. -

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 619 of the GAA protein (p.Ser619Asn). This variant is present in population databases (rs753269119, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 16838077, 22990675, 24158270, 25998610, 26946079). ClinVar contains an entry for this variant (Variation ID: 370146). 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: 19862843). This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14643388, 21471980, 25213570, 27363342, 29124014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1856G>A variant in GAA is a missense variant predicted to cause substitution of serine by asparagine at amino acid 619 (p.Ser619Asn). At least five probands with symptoms consistent with late-onset-Pompe disease have been reported with this variant (PMIDs 24158270, 16838077, 25052852, 37087815,22194990), two with documented deficiency of GAA activity (PMIDs 24158270, 16838077) (PP4_Moderate). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G (PMID: 25052852). The other three patients are compound heterozygous with unknown phase for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.-32-13T>G, c.1655T>C (p.Leu552Pro) or c.1927G>A (p.Gly643Arg), respectively (PMIDs: 37087815, 16838077, 24158270) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.0 is 0.0001875 (17/90678 alleles) in South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in <5% GAA activity in cells and <5% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 16838077 and 19862843)(PS3_Moderate). The computational predictor REVEL gives a score 0.744 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: 370146; 2-star review status) with 10 submitters classifying the variant as pathogenic, and 2 as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) -

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Aug 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced total enzyme amount and in vitro enzyme activity (PMID: 16838077); 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: 34530085, 31589614, 33202836, 23668440, 16838077, 26946079, 31086307, 21471980, 25052852, 14643388, 19862843, 22194990, 22980766, 22990675, 27363342, 25213570, 25998610, 33073007, 29124014, 24158270) -

Abnormality of metabolism/homeostasis

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.98

Loss of disorder (P = 0.1076);Loss of disorder (P = 0.1076);

MVP

1.0

MPC

0.52

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.94

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

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