17-80113242-G-A

Variant names:

• chr17-80113242-G-A
• rs1800309
• NM_000152.5:c.2065G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.2065G>A​(p.Glu689Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,601,260 control chromosomes in the GnomAD database, including 2,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (308 hom., cov: 34)
  • Exomes 𝑓: 0.046 (2661 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts P:1 B:14 O:3
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000152.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset, glycogen storage disease due to acid maltase deficiency, infantile onset.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015834868).
• BP6: Variant 17-80113242-G-A is Benign according to our data. Variant chr17-80113242-G-A is described in ClinVar as [Benign, other]. Clinvar id is 4030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80113242-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.2065G>A	p.Glu689Lys	missense_variant	Exon 15 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2065G>A	p.Glu689Lys	missense_variant	Exon 15 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6657 AN: 152194 Hom.: 305 Cov.: 34

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0556 AC: 12525 AN: 225448 AF XY: 0.0556

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.0621

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0457 AC: 66223 AN: 1448948 Hom.: 2661 Cov.: 35 AF XY: 0.0463 AC XY: 33325 AN XY: 719752

African (AFR) AF: 0.0195 AC: 651 AN: 33310

American (AMR) AF: 0.0272 AC: 1175 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1102 AN: 25806

East Asian (EAS) AF: 0.257 AC: 10060 AN: 39104

South Asian (SAS) AF: 0.0612 AC: 5132 AN: 83920

European-Finnish (FIN) AF: 0.0670 AC: 3425 AN: 51086

Middle Eastern (MID) AF: 0.0247 AC: 142 AN: 5746

European-Non Finnish (NFE) AF: 0.0374 AC: 41410 AN: 1106876

Other (OTH) AF: 0.0522 AC: 3126 AN: 59904

GnomAD4 genome AF: 0.0438 AC: 6671 AN: 152312 Hom.: 308 Cov.: 34 AF XY: 0.0456 AC XY: 3396 AN XY: 74472

African (AFR) AF: 0.0205 AC: 853 AN: 41580

American (AMR) AF: 0.0389 AC: 595 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.238 AC: 1232 AN: 5168

South Asian (SAS) AF: 0.0691 AC: 334 AN: 4832

European-Finnish (FIN) AF: 0.0653 AC: 694 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2691 AN: 68014

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0481 Hom.: 651

Bravo AF: 0.0399

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.0348 AC: 299

ExAC AF: 0.0515 AC: 6210

Asia WGS AF: 0.149 AC: 520 AN: 3478

ClinVar

Significance: Benign; other

Submissions summary: Pathogenic:1 Benign:14 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type II Benign:6 Other:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- pseudodeficiency allele

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu689Lys variant in GAA has been reported as a benign and likely benign variant for Glycogen Storage Disease II in ClinVar (Variation ID: 4030). This variant has been identified in 5.490% (13805/251476) of chromosomes, including 757 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800309). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. It is a known pseudodeficiency allele that causes false-positive results in GAA deficiency enzyme assays (PMID: 20080426, 18301443). In summary, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1 (Richards 2015). -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Benign (Pseudodeficiency Allele) and reported on 08-15-2018 by Invitae. 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. -

not specified Benign:5

-

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported in multiple Invitae PIN participants. Variant interpreted as Benign (Pseudo deficiency allele) most recently on 9/29/2020 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. -

Acid alpha-glucosidase, allele 4 Pathogenic:1

Sep 01, 1996

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.60	D;D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.58	.;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.35	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.092	B;B
Vest4		0.080
MPC		0.14
ClinPred		0.0035	T
GERP RS		1.5
Varity_R		0.086
gMVP		0.53
Mutation Taster		=98/2	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

Publications

Loading publications...

Other links and lift over

dbSNP: rs1800309; hg19: chr17-78087041; COSMIC: COSV56407168; COSMIC: COSV56407168;