rs786204645

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePM3_StrongPS3_SupportingPM5PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2104C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 702 (p.Arg702Cys). At least 1 patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PMID:14972326). At least 1 patient with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID:25687148). Other patients with this variant who were noted to have Pompe disease were found in the literature, but enzyme activity was not discussed (PMID:20308911, 31086307) (PP4_Moderate). This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and -32-13T>G a pathogenic variant by the ClinGen Lysosomal Diseases VCEP (phase unknown)(PMID:20308911, 24158270) and 1 individual was compound heterozygous for the variant and c.2481+110_2646+39del (confirmed in trans by parental/family testing)(PMID:14972326). Two individuals were homozygous for the variant (PMID:25687148, 31086307), meetings the criteria for PM3_Strong. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/254192 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS resulted in less than 2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID:14972326, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants [c.2105G>T (p.Arg702Leu, ClinVar Variation ID: 92472) and c.2105G>A (p.Arg702His, ClinVar Variation ID: 426278)], in the same codon have been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 189040). 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): PP4_Moderate, PM3_Strong, PM2_Supporting, PS3_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 11, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274304/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 5.87

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 11 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.

PM5

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.2104C>T	p.Arg702Cys	missense_variant	Exon 15 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.2104C>T	p.Arg702Cys	missense_variant	Exon 15 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1448162

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719058

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:

0.0000239

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:9

Oct 28, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Apr 22, 2023

Baylor 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.Arg702Cys variant in GAA has been reported in 5 individuals (including 1 from Italy and 1 from France) with Glycogen Storage Disease II (PMID: 14972326, 25786784, 16917947, 24158270, 22704482) and has been identified in 0.011% (1/8702) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786204645). 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 Invitae in ClinVar (Variation ID: 189040). In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Arg702Cys variant may impact GAA activity (PMID: 14972326, 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 and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg702Cys variant is pathogenic (PMID: 24158270, 22704482, 14972326). Two additional variants at the the same position, p.Arg702His and p.Arg702Leu, have been reported likely pathogenic in association with disease in ClinVar (Variation ID: 426278, 92472). The phenotype of individuals heterozygous with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays with relevant tissue (PMID: 24158270, 22704482, 14972326). 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). -

May 03, 2021

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.2104C>T (p.Arg702Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 222816 control chromosomes. c.2104C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Montalvo_2004, Angelini_2012, Chen_2015). These data indicate that the variant is 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 (Montalvo_2004). Three 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. -

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 702 of the GAA protein (p.Arg702Cys). This variant is present in population databases (rs786204645, gnomAD 0.005%). This missense change has been observed in individual(s) with findings that are highly specific for GAA-related conditions (PMID: 14972326, 24158270). 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: 189040). 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: 14972326, 19862843). This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18211760, 18425781, 26310554). 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. -

Nov 16, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.2104C>Tp.Arg702Cys variant in GAA gene has been previously observed in homozygous and compound heterozygous states in multiple individuals affected with glycogen storage related disorders Montalvo AL et al.,2004; HernándezArévalo P et al.,2021. Experimental studies have shown that this missense variant is associated with reduced enzyme activity as compared to wild-type function of GAA Montalvo AL et al.,2004; Flanagan JJ et al. 2009. The p.Arg702Cys is present with allele frequency of 0.00% in gnomAD exomes. This variant has been submitted to ClinVar as Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT- Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg702Cys in GAA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 702 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jan 11, 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.2104C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 702 (p.Arg702Cys). At least 1 patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PMID: 14972326). At least 1 patient with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID: 25687148). Other patients with this variant who were noted to have Pompe disease were found in the literature, but enzyme activity was not discussed (PMID: 20308911, 31086307) (PP4_Moderate). This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and -32-13T>G a pathogenic variant by the ClinGen Lysosomal Diseases VCEP (phase unknown)(PMID: 20308911, 24158270) and 1 individual was compound heterozygous for the variant and c.2481+110_2646+39del (confirmed in trans by parental/family testing)(PMID: 14972326). Two individuals were homozygous for the variant (PMID: 25687148, 31086307), meetings the criteria for PM3_Strong. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/254192 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS resulted in less than 2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID: 14972326, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants [c.2105G>T (p.Arg702Leu, ClinVar Variation ID: 92472) and c.2105G>A (p.Arg702His, ClinVar Variation ID: 426278)], in the same codon have been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 189040). 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): PP4_Moderate, PM3_Strong, PM2_Supporting, PS3_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 11, 2025) -

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Sep 01, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The second sequence change is a missense variant in exon 15, c.2104C>T (p.Arg702Cys). The p.Arg702Cys change affects a highly conserved amino acid residue located in a domain of the GAA protein that is known to be functional. The p.Arg702Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database in one heterozygous individual which corresponds to a population frequency of 0.00039% (dpSNP rs786204645). This sequence change has been reported in individuals with glycogen storage disease II in the homozygous state and in the compound heterozygous state with other variants classified as pathogenic including the c.-32-13T>G sequence change (PMID: 34020684, 27858611, 24158270, 31086307, 14972326). Additionally, other sequence changes that affect this same amino acid have been reported in individuals with GAA-related disorders (18211760, 18425781, 26310554). Experimental studies have shown that this sequence change impacts the function of the GAA protein (PMID: 14972326, 19862843). Based on these collective evidences, the c.2104C> variant is classified as pathogenic. -

Dec 11, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional analysis found this variant is associated with significantly reduced enzyme activity compared to wild-type (Montalvo AL et al., 2004); 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, 31086307, 24158270, 14972326, 29046207, 32959227, 28856460, 31342611, 30922962, 25786784, 16917947, 31392188, 33301762, 34530085, 18425781) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

1.0

MutPred

0.98

Gain of methylation at K697 (P = 0.0334);Gain of methylation at K697 (P = 0.0334);

MVP

1.0

MPC

0.63

ClinPred

1.0

GERP RS

4.9

Varity_R

0.98

gMVP

0.97

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