17-80112920-G-T

Variant names:

• chr17-80112920-G-T
• rs368438393
• NM_000152.5:c.1933G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PS3_Moderate PM3_Strong PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1933G>T variant in GAA is a missense variant predicted to cause substitution of aspartic acid, by tyrosine at amino acid 645 (p.Asp645Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000335 (2/59698 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001) meeting this criterion (PM2_Supporting). This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and pathogenic variants (c.-32-13T>G and c.525delT) none of those were confirmed in trans. (PMID:27711114, 17616415, 24715333). Two individuals were homozygous for the variant (PMID:38250073) (PM3_Strong).At least three patients with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts or were noted to have deficient GAA activity but results were not provided (PMID:17616415, 24715333). Another four patients were reported to be on enzyme replacement therapy for Pompe disease (PMID:38250073, 29573408, 27711114, 24715333) (PP4_Moderate). Expression of the variant in COS cells resulted in 0% wild type GAA activity in cells and medium and evidence of abnormal GAA synthesis and processing), variant to be described as Class B (“potentially less severe), indicating that this variant may impact protein function (PMID:18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants (c.1933G > A, p.Asp645Asn, ClinVar Variation ID 188728, PMID:9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565) and (c.1933G>C, p.Asp645His, ClinVar Variation ID 189013, PMID: (PMID:12897283, 7695647) in the same codon have been classified as pathogenic and likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5).There is a ClinVar entry for this variant (Variation ID: 556386)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, PP4_Moderate, PS3_Moderate, PM5, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369905/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.82
• Publications: 49 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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	c.1933G>T	p.Asp645Tyr	missense_variant	Exon 14 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1933G>T	p.Asp645Tyr	missense_variant	Exon 14 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 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

GnomAD2 exomes AF: 0.00000825 AC: 2 AN: 242414 AF XY: 0.0000152

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458274 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725104

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.0000225 AC: 1 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110854

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Dec 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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.Asp645Tyr variant in GAA has been reported in four individuals with glycogen storage disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 18425781, 17616415; DOI: 10.1016/j.jns.2015.08.1211) and has been identified in 0.007% (1/15154) of African chromosomes and 0.003% (1/33952) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). 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 likely pathogenic by Counsyl (VariationID: 556386). In vitro studies using cells transfected with the variant provide some evidence that the p.Asp645Tyr variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Three additional pathogenic variants, resulting in a different amino acid change at the same position (p.Asp645Asn, p.Asp645His, and p.Asp645Glu) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 188728, 189013, 4029). 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 phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <20% of wild type, consistent with disease (PMID: 17616415). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17616415, https://doi.org/10.1016/j.jns.2015.08.1211) and in individuals with glycogen storage disease II silghtly increases the likelihood that the p.Asp645Tyr variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on functional studies demonstrating a potential impact on the protein, previous reports of other pathogenic variants at the same location, and the presence of the variant in combination with a pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3_Supporting, PP3, PP4 (Richards 2015). -

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 645 of the GAA protein (p.Asp645Tyr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 17616415, 24715333). ClinVar contains an entry for this variant (Variation ID: 556386). 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%. This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). 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. -

Dec 19, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1933G>T variant in GAA is a missense variant predicted to cause substitution of aspartic acid, by tyrosine at amino acid 645 (p.Asp645Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000335 (2/59698 alleles) in the Admixed American population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001) meeting this criterion (PM2_Supporting). This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and pathogenic variants (c.-32-13T>G and c.525delT) none of those were confirmed in trans. (PMID: 27711114, 17616415, 24715333). Two individuals were homozygous for the variant (PMID: 38250073) (PM3_Strong). At least three patients with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 24715333). Another four patients were reported to be on enzyme replacement therapy for Pompe disease (PMID: 38250073, 29573408, 27711114, 24715333) (PP4_Moderate). Expression of the variant in COS cells resulted in 0% wild type GAA activity in cells and medium and evidence of abnormal GAA synthesis and processing), variant to be described as Class B (“potentially less severe), indicating that this variant may impact protein function (PMID: 18425781) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants (c.1933G > A, p.Asp645Asn, ClinVar Variation ID 188728, PMID: 9535769, 15145338, 16860134, 17723315, 23601496, 25139343, 26497565) and (c.1933G>C, p.Asp645His, ClinVar Variation ID 189013, PMID: (PMID: 12897283, 7695647) in the same codon have been classified as pathogenic and likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 556386) 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, PP4_Moderate, PS3_Moderate, PM5, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) -

GAA-related disorder Pathogenic:1

Dec 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAA c.1933G>T variant is predicted to result in the amino acid substitution p.Asp645Tyr. This variant, along with a second pathogenic GAA variant, has been reported in multiple individuals with glycogen storage disease 2 (Gort et al. 2007. PubMed ID: 17616415; van Gelder et al. 2015. PMID: 24715333; Figueroa-Bonaparte et al. 2016 PMID: 27711114; Ebbink et al. 2018. PMID:29573408; Amiñoso et al. 2022. PubMed ID: 34530085). In the fibroblasts of an individual that was also heterozygous for the c.-32-13T>G variant had residual GAA activity of ~20% (Gort et al. 2007. PubMed ID: 17616415). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78086719-G-T). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Mar 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with no detectable enzyme activity (PMID: 18425781); 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: 30281819, 26944269, 35787971, 31342611, 30049495, 22253258, 19343043, 24715333, 17616415, 29573408, 18425781, 34530085) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H
PhyloP100		9.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		1.0		Loss of stability (P = 0.1513);Loss of stability (P = 0.1513);
MVP		0.97
MPC		0.60
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs368438393; hg19: chr17-78086719;