rs757700700

Positions:

chr17-80105872-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_StrongPS3PM2PP4

This summary comes from the ClinGen Evidence Repository: This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763C > T (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the 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: PS3, PM2, PM3_Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274477/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13U:1O:1

Conservation

PhyloP100: -0.0370

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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.670C>T	p.Arg224Trp	missense_variant	3/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.670C>T	p.Arg224Trp	missense_variant	3/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

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:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243354

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132516

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000249

AC:

AN:

1447026

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

719062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2018	Variant summary: GAA c.670C>T (p.Arg224Trp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of 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 2.2e-05 in 269992 control chromosomes (gnomAD and publications). The variant, c.670C>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Habbal_2013, Pipo_2003, Pittis_2003, Pittis_2008). These data indicate that the variant is likely to be associated with disease. Multiple publications have functionally assessed the variant indicating the variant significantly impedes GAA enzymatic activity (Angelini_2012, Pipo_2003, Pittis_2003). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic or uncertain significance without additional evidence to independently evaluate. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 21, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the GAA protein (p.Arg224Trp). This variant is present in population databases (rs757700700, gnomAD 0.004%). This missense change has been observed in individuals with Pompe disease (PMID: 12923862, 14643388, 18429042, 25026126, 29422078). ClinVar contains an entry for this variant (Variation ID: 189188). 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: 12923862, 14643388, 19862843). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 04-29-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 03, 2020	This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763Câ€Š>â€ŠT (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the 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: PS3, PM2, PM3_Strong, PP4. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Arg224Trp variant in GAA has been reported in the compound heterozygous state in 6 individuals with Glycogen Storage Disease II (PMID: 25673129, 12923862, 25026126, 23632174, 14643388), and has been identified 0.005% (6/127580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757700700). 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 as a VUS by EGL Genetic Diagnostics, a likely pathogenic variant by Counsyl, and a pathogenic variant by Invitae and Integrated Genetics in ClinVar (Variation ID: 189188). In vitro functional studies provide some evidence that the p.Arg224Trp variant may impact GAA activity (PMID: 19862843, 14643388, 12923862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg224Trp variant is pathogenic (PMID: 12923862, 25673129, 25026126). 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 individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2022	The GAA c.670C>T (p.Arg224Trp) missense variant results in the substitution of arginine at amino acid position 224 with tryptophan. Across a selection of the available literature, the c.670C>T variant has been identified in a compound heterozygous state in at least six individuals affected with glycogen storage disease, type II (Pipo et al. 2003; Pittis et al. 2003; Zouheir Habbal et al. 2013; Aykut et al. 2014; Parini et al. 2018). Affected individuals show reduced alpha-glucosidase activity and onset of the disease is influenced by the second pathogenic variant found in trans. The c.670C>T variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000047 in the European (non-Finnish) population (version 2.1.1). Functional studies demonstrated that when the c.670C>T variant protein was expressed in cells, glucosidase enzyme activity was reduced to 2-10% of wild-type activity (Pittis et al. 2003; Pipo et al. 2003; Flanagan et al. 2009). Based on the available evidence, the c.670C>T (p.Arg224Trp) variant is classified as pathogenic for glycogen storage disease, type II. -

not provided

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2024	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 14643388, 33560568, 19862843); 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: 14643388, 25026126, 19862843, 12923862, 18429042, 26830551, 30564623, 35050212, 31086307, 36246652, 30275481, 19343043, 22253258, 33741225, 34530085, 33560568, 29422078, 34852371, 23632174, 22521436) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 29, 2021	- -

GAA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

The GAA c.670C>T variant is predicted to result in the amino acid substitution p.Arg224Trp. This variant has been reported with a second GAA variant in many individuals with autosomal recessive glycogen storage disease (Pittis et al 2003. PubMed ID: 12923862; Zouheir Habbal et al 2013. PubMed ID: 23632174; Parini et al 2018. PubMed ID: 29422078). This variant is reported in 0.0047% of alleles in individuals of European (non-Finnish) descent in gnomAD. The CLinGen Lysosomal Storage Disorder Expert Panel interprets this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Benign

-0.0013

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

4.1

.;H;H

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.2

.;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.92, 0.93

MutPred

0.87

Gain of catalytic residue at Q225 (P = 0.057);Gain of catalytic residue at Q225 (P = 0.057);Gain of catalytic residue at Q225 (P = 0.057);

MVP

0.98

MPC

0.55

ClinPred

1.0

GERP RS

-0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.96

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