17-80112072-G-A

Variant names:

• chr17-80112072-G-A
• rs1800307
• NM_000152.5:c.1726G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 6P and 16B. PM1 PM5 PP2 PP3 BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.1726G>A​(p.Gly576Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,613,972 control chromosomes in the GnomAD database, including 806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0091 (83 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (723 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:11 O:3
• Conservation: PhyloP100: 9.30
• Publications: 102 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 -10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000152.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80112073-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526516.
• 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 due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP6: Variant 17-80112072-G-A is Benign according to our data. Variant chr17-80112072-G-A is described in ClinVar as Benign|other. ClinVar VariationId is 92467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1726G>A	p.Gly576Ser	missense_variant	Exon 12 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1726G>A	p.Gly576Ser	missense_variant	Exon 12 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1380 AN: 152194 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0177 AC: 4439 AN: 251298 AF XY: 0.0175

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00905

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00826 AC: 12080 AN: 1461660 Hom.: 723 Cov.: 31 AF XY: 0.00885 AC XY: 6438 AN XY: 727166

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.00928 AC: 415 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26126

East Asian (EAS) AF: 0.170 AC: 6749 AN: 39692

South Asian (SAS) AF: 0.0273 AC: 2352 AN: 86258

European-Finnish (FIN) AF: 0.0133 AC: 709 AN: 53312

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000943 AC: 1048 AN: 1111926

Other (OTH) AF: 0.0127 AC: 766 AN: 60382

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152312 Hom.: 83 Cov.: 33 AF XY: 0.0105 AC XY: 783 AN XY: 74470

African (AFR) AF: 0.000962 AC: 40 AN: 41576

American (AMR) AF: 0.0106 AC: 163 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.147 AC: 760 AN: 5174

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4824

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68012

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00698 Hom.: 275

Bravo AF: 0.00842

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0179 AC: 2170

Asia WGS AF: 0.0810 AC: 283 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Significance: Benign; other

Submissions summary: Benign:11 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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. -

May 15, 2017

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Pseudodeficiency allele c.1726 G>A (p.Gly576Ser), which interferes with enzyme activity toward artificial substrates, is relatively common in Asian as well as other populations studied as part of newborn screening programs. Pseudodeficiency

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 03-18-2020 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. -

Dec 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- pseudodeficiency allele

not provided Benign:4

Nov 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 03, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.1726G>A (p.Gly576Ser) variant involves the alteration of a conserved nucleotide resulting in a missense substitution in the glycoside hydrolase superfamily domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC in 2266 of 121736 control chromosomes (124 homozygotes) from all ethnicities, but was predominantly observed in the East Asian subpopulation at a frequency of 0.144416 (1244/8614; 109 homozygotes). This frequency is about 34 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), strongly suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant and its haplotype complex, p.[G576S; E689K], are widely regarded as a variant causing pseudodeficiency of alfa-glucosidase. The subjects who carried the p.[G576S;E689K] in homozygous state or compound heterozygous state with a truncating variant were not found to clinically manifest Pompe disease, yet they had a reduced enzymatic activity (Kroos_EJHG_2008). In addition, this variant has also been found in cis with two known pathogenic variants (p. Asp645Glu and p.Trp746Cys) in patients with Pompe disease (Yang_MGM_2011), strongly suggesting for a benign outcome. In vitro functional studies are consistent with this variant being a functional polymorphism; this variant maintains a residual activity and it can significantly reduce the functional activity of a potentially pathogenic variant when found in cis (Pipo_Peditr Neurol_2003; Yang_MGM_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9266392, 21644219, 18301443, 14643388, 17805474, 28725570) -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

May 03, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 30, 2023

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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.6	H;H
PhyloP100		9.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.34
MPC		0.54
ClinPred		0.078	T
GERP RS		4.7
Varity_R		0.94
gMVP		0.93
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800307; hg19: chr17-78085871; COSMIC: COSV56407575; COSMIC: COSV56407575;