chr17-80104857-G-A

Variant names:

• chr17-80104857-G-A
• rs1800299
• NM_000152.5:c.271G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.271G>A missense variant in GAA (p.Asp91Asn) has a highest population minor allele frequency in gnomAD v2.1.1 of 0.03291 (4183/127102 alleles; 70 homozygotes) in the European non-Finnish population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.396 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. In addition, the computational splice predictors SpliceAI and varSEAK predict that the variant has no impact on splicing (BP4). This variant is frequently described as a “pseudodeficiency” variant in the literature. It has been identified as the amino acid substitution responsible for the GAA*2 alloenzyme (also known as GAA2) (PMID:2203258). GAA*2 was identified by its faster migration on starch gel electrophoresis compared to the GAA*1 alloenzyme (PMID:2688539). In addition, compared to GAA*1, GAA*2 has a 10 fold higher Km for glycogen, but similar Km for maltose and 4-MUG (PMID:2688539). No differences between the processing of GAA*2 and GAA*1 were noted on Western blot of protein from fibroblasts homozygous for either alloenzyme (PMID:2688539). Furthermore, comparable amounts of glycogen were found in the lysosomes of the GAA*1 and GAA*2 homozygous cell lines, and there was no evidence of abnormal lysosomal glycogen storage in GAA*2 fibroblasts on electron microscopy (PMID:2688539). When expressed in SV40-transformed GAA-deficient fibroblasts, c.271G>A (p.Asp91Asn) has similar GAA activity to wild type when 4-MUG is used as the substrate (PMID:2203258). Studies in cells from patients show a difference in GAA activity depending on the substrate used. In cells from individuals who are homozygous, or compound heterozygous for the variant and a known pathogenic GAA variant, false positives arose when glycogen was used as the substrate in the leukocyte assay, while the expected result was obtained when 4-MUG was used as the substrate in either the leukocyte or fibroblast assays (PMID:19387865, 33162552). Evidence from the crystal structures of native and recombinant GAA indicate that Asp91 is involved in a sugar binding site, which could explain why this variant binds carbohydrate less effectively (PMID:29061980; https://www.biorxiv.org/content/10.1101/212837v1 ). In addition, while the computational splice site predictors SpliceAI and varSEAK predict no impact on splicing, a mini-gene assay indicated that the variant results in exon 2 exclusion in about 30% of transcripts (PMID:31301153). As an explanation for how the biochemical features of this variant result in no clinical features, substrate concentrations are usually far below that required for saturation of the enzyme. A reduction in enzyme activity brought about by decrease in Vmax, or increase in Km, would be compensated for by an increase in substrate concentration, restoring the normal turnover rate and establishing an equilibrium substrate concentration (PMID:2688539).In patients with Pompe disease, c.271G>A has been found in cis with other variants that have been classified as pathogenic by the ClinGen LSD VCEP, p.Cys103Gly (PMID:16838077, 33073003) and c.877G>A (p.Gly293Arg) (PMID:27189384).There is a ClinVar entry for this variant (Variation ID: 4020) with eight submitters classifying the variant as benign, two as likely benign, and two as “other”. In summary, based on the evidence available to date, this variant meets the criteria to be classified as benign for Pompe disease. However, it is important to note that GAA activity may be in the patient range in individuals who are homozygous for the variant, or compound heterozygous for the variant and a pathogenic GAA variant, if glycogen is used as a substrate. Careful evaluation and use of 4-MUG as the substrate is necessary to provide accurate results. Therefore, this variant is classified as “other” to ensure that an explanation for deficient enzyme activity in the context of a clinically benign variant is highlighted. GAA-specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA116586/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.021 (61 hom., cov: 32)
  • Exomes 𝑓: 0.029 (746 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:12 O:5
• Conservation: PhyloP100: 9.79
• Publications: 54 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: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.271G>A	p.Asp91Asn	missense	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.271G>A	p.Asp91Asn	missense	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.271G>A	p.Asp91Asn	missense	Exon 2 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.271G>A	p.Asp91Asn	missense	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.271G>A	p.Asp91Asn	missense	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.271G>A	p.Asp91Asn	missense	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3261 AN: 152192 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0203 AC: 5048 AN: 248310 AF XY: 0.0201

Gnomad AFR exome AF: 0.00613

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0326

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0290 AC: 42319 AN: 1460562 Hom.: 746 Cov.: 31 AF XY: 0.0284 AC XY: 20654 AN XY: 726596

African (AFR) AF: 0.00439 AC: 147 AN: 33468

American (AMR) AF: 0.0125 AC: 558 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 375 AN: 26120

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39678

South Asian (SAS) AF: 0.00811 AC: 699 AN: 86222

European-Finnish (FIN) AF: 0.0179 AC: 939 AN: 52360

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5766

European-Non Finnish (NFE) AF: 0.0343 AC: 38142 AN: 1111880

Other (OTH) AF: 0.0234 AC: 1410 AN: 60374

GnomAD4 genome AF: 0.0214 AC: 3260 AN: 152310 Hom.: 61 Cov.: 32 AF XY: 0.0204 AC XY: 1519 AN XY: 74470

African (AFR) AF: 0.00633 AC: 263 AN: 41572

American (AMR) AF: 0.0186 AC: 285 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4826

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0343 AC: 2333 AN: 68024

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0274 Hom.: 105

Bravo AF: 0.0203

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0315 AC: 271

ExAC AF: 0.0204 AC: 2476

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0319

EpiControl AF: 0.0307

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Benign:12 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:5 Other:3

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign, Pseudo-deficiency allele and reported, most recently on 12-16-2020 by Lab or GTR ID 500031. 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.

Jan 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

pseudodeficiency allele

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 08-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Jun 03, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 29, 2015

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not provided Benign:3 Other:2

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Associated with pseudodeficiency of alpha-glucosidase enzyme. Homozygosity for D91N or compound heterozygosity for D91N and a pathogenic variant results in low enzyme activity but no clinical symptoms of Pompe disease (Martiniuk et al., 1990; Tajima et al., 2007; Kroos et al., 2008); This variant is associated with the following publications: (PMID: 31301153, 29181627, 25998610, 20080426, 2203258)

Dec 14, 2017

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: flagged submission

Collection Method: phenotyping only

Variant reported in multiple Invitae PIN participants. Variant interpreted as Benign (Pseudo deficiency allele) most recently on 10/30/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Jun 02, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

The GAA gene is associated with Pompe disease; however, this variant is not associated with disease. It is known to interfere with assays for GAA enzyme activity and is therefore called a "pseudodeficiency allele". Even individuals with two copies of this variant do not have Pompe disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Acid alpha-glucosidase, allele 2 Benign:1

Oct 28, 2012

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Cardiovascular phenotype Benign:1

Dec 28, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.40
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.40
MPC		0.53
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.71
gMVP		0.83
Mutation Taster		=56/44	polymorphism (auto)

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: rs1800299; hg19: chr17-78078656; COSMIC: COSV56408897; COSMIC: COSV56408897;