17-80118668-G-T

Variant names:

• chr17-80118668-G-T
• rs765718882
• NM_000152.5:c.2662G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.2662G>T (p.Glu888Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00027 in the East Asian population, meeting PM2. At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044), and another is homozygous for the variant (PMID 17723315). This data meets PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). There is a ClinVar entry for this variant (Variation ID: 578595) with two submitters classifying the variant as pathogenic. In summary, this 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: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815829/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.147
• Publications: 30 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 13 ACMG points.

• PVS1: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2662G>T	p.Glu888*	stop_gained	Exon 19 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2662G>T	p.Glu888*	stop_gained	Exon 20 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2662G>T	p.Glu888*	stop_gained	Exon 19 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2662G>T	p.Glu888*	stop_gained	Exon 19 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2662G>T	p.Glu888*	stop_gained	Exon 20 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.2662G>T	p.Glu888*	stop_gained	Exon 19 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.0000200 AC: 5 AN: 250228 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460338 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726462

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

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

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Jun 24, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu888*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs765718882, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with glycogen storage disease, type II (GSDII), also known as Pompe disease (PMID: 16531044, 17723315, 18458862, 20080426, 21644219, 28032299, 28394184). ClinVar contains an entry for this variant (Variation ID: 578595). For these reasons, this variant has been classified as Pathogenic.

May 04, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.2662G>T (p.Glu888Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00027 in the East Asian population, meeting PM2. At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044), and another is homozygous for the variant (PMID 17723315). This data meets PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). There is a ClinVar entry for this variant (Variation ID: 578595) with two submitters classifying the variant as pathogenic. In summary, this 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: PVS1, PM2, PM3, PP4.

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.Glu888Ter variant in GAA has been reported in at least 8 individuals with glycogen storage disease (PMID: 25526786, 21232767, 18458862, 17723315, 16531044) and has been identified in 0.027% (5/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765718882). 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 Integrated Genetics (VariationID: 578595). This nonsense variant leads to a premature termination codon at position 888, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. The phenotype of individuals homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in lymphocytes and fibroblasts being <10% of wild type, consistent with disease (PMID: 25526786, 21232767, 17723315, 18458862). In addition, the presence of this variant in individuals with glycogen storage disease has been observed in combination with reported pathogenic and likely pathogenic variants (VariationID: 265160, 4027, 4029, 4032; PMID: 25526786, 21232767, 18458862, 17723315, 16531044). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the prediction that it will cause loss of function of the GAA gene and the presence of the variant in combination with numerous other pathogenic variants in affected individuals with phenotypes highly specific for GAA. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4_moderate, PM2 (Richards 2015).

Aug 19, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3, PP4

Dec 20, 2018

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.2662G>T (p.Glu888X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 245054 control chromosomes (gnomAD). The variant, c.2662G>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in both compound heterozygotes and homozygotes (Kostera-Pruszczyk_2006, Liu_2014, Chen_2017), and is one of the most common disease variant in Northern Chinese. These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

Feb 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 07, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32711049, 30275481, 31743840, 31086307, 28032299, 20080426, 25626711, 17723315, 27417441, 25455803, 25526786, 24269976, 18458862, 30943998, 16531044, 21644219, 25525159, 28394184, 21232767)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Benign	0.87
Eigen	Benign	-0.55
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
PhyloP100		0.15
Vest4		0.82
GERP RS		-9.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs765718882; hg19: chr17-78092467;