17-80112928-C-G

Position:

• chr17-80112928-C-G

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM3 PS3_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815554/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: -1.20

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 7 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/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1941C>G	p.Cys647Trp	missense_variant	14/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1941C>G	p.Cys647Trp	missense_variant	14/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33

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: 3 AN: 242552 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 131934

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: 9 AN: 1458152 Hom.: 0 Cov.: 33 AF XY: 0.00000690 AC XY: 5 AN XY: 725018

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: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

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.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7

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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 -

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	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.8	H;H
PrimateAI	Pathogenic	0.82	D
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	D
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

Other links and lift over

dbSNP: rs776948121; hg19: chr17-78086727;