17-80112928-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000152.5(GAA):c.1941C>G(p.Cys647Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,610,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C647F) has been classified as Likely pathogenic.

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:8

Conservation

PhyloP100: -1.20

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 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000152.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80112927-G-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 1219617.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-80112928-C-G is Pathogenic according to our data. Variant chr17-80112928-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 550327.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80112928-C-G is described in Lovd as [Pathogenic]. Variant chr17-80112928-C-G is described in Lovd as [Likely_pathogenic]. Variant chr17-80112928-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1941C>G	p.Cys647Trp	missense_variant	14/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.1941C>G	p.Cys647Trp	missense_variant	14/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

242552

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

131934

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:

0.0000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1458152

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725018

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2021	Variant summary: GAA c.1941C>G (p.Cys647Trp) 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 allele was found at a frequency of 1.2e-05 in 242562 control chromosomes (gnomAD and publication data). c.1941C>G has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Huie_1994, Huie_1998, McCready_2007, Kishnani_2019). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in absent enzyme activity from transfected cells and fibroblasts (Huie_1994, Huie_1998, McCready_2007). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 25, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 15, 2022	The NM_000152.5:c.1941C>G variant in GAA is a missense variant that is predicted to result in substitution of cysteine by tryptophan at amino acid 647 (p.Cys647Trp). At least 10 patients with this variant have been reported to have Pompe disease including two with documented laboratory values showing deficiency of GAA, one of whom also had reported symptoms consistent with infantile onset Pompe disease (PMID: 7981676, 9535769, 17723315) (meeting PP4_Moderate), three patients with reported symptoms consistent with infantile onset Pompe disease (PMID: 7981676, 19588081, 22658377, 31510962), one patient on enzyme replacement therapy (PMID: 31086307) (all meeting PP4). Four patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic for Pompe disease including c.-32-13T>G (PMID: 25681614, 31931849; 2 patients), c.2481+110_2646+39del (exon 18 deletion, PMID: 7981676), and c.1655T>C (p.Leu552Pro) (PMID: 19588081), all phase unconfirmed. In another patient, the variant is confirmed in trans with an allele containing two pathogenic variants, c.1456_1468del (p.Ala486fsTer30) (confirmed de novo) and c.2238G>C (p.Trp746Cys) (PMID: 7981676), and two patients are homozygous for the variant (PMID: 9535769, 31510962) (PM3_Very Strong). In addition, two patients are compound heterozygous for the variant and either c.1846G>A (p.Asp616Asn) (PMID: 31086307) or c.1781G>C (p.Arg594Pro) (PMID: 19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. In another patient, no second variant was found (PMID: 25681614). When expressed in GAA-deficient SV40 immortalized fibroblasts, the variant resulted in <1% GAA activity compared to the normal control ( PMID: 9535769) (PS3_Supporting).The computational predictor REVEL gives a score of 0.802 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00002 (3/124712 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Of note, the highest population minor allele frequency in gnomAD v2.1.1 is in the "other" population, 0.00014 (1/7006 alleles) which also meets the PM2_Supporting threshold. There is a ClinVar entry for this variant (Variation ID: 550327). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on Nov. 15, 2022. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 647 of the GAA protein (p.Cys647Trp). This variant is present in population databases (rs776948121, gnomAD 0.002%). This missense change has been observed in individual(s) with infantile onset Pompe disease (PMID: 7981676, 9535769, 17723315, 19588081, 22658377, 25681614). 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: 550327). 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: 7981676). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Cys647Trp variant in GAA has been reported in at least seven individuals with glycogen storage disease II (PMID: 9535769, 17723315, 19588081, 25681614) and has been Identified in 0.002% (3/124712) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776948121). 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 in ClinVar as Pathogenic by Invitae and as Likely Pathogenic by Counsyl (VariationID: 550327). In vitro functional studies provide some evidence that the p.Cys647Trp variant may impact protein function (PMID: 9535769). However, these types of assays may not accurately represent biological function. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 9535769, 17723315). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in homozygous individuals in individuals with glycogen storage disease II increases the likelihood that the p.Cys647Trp variant is pathogenic (PMID: 9535769, 17723315). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on its presence in affected individuals in combination with other pathogenic variants or in a homozygous state, in vitro functional studies demonstrating markedly reduced expression, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 17, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 moderated, PP3 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 13, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2020

Expression studies found that the variant abolished alpha-glucosidase activity compared to wild-type (Huie et al., 1994); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31086307, 7981676, 25681614, 19588081, 22658377, 17723315, 9535769) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.39

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.54

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.8

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-11

D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.92

Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);

MVP

0.99

MPC

0.63

ClinPred

1.0

GERP RS

-3.4

Varity_R

0.99

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