rs1800307

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM5PP3BP6_Very_StrongBA1

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. G576A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 83 hom., cov: 33)

Exomes 𝑓: 0.0083 ( 723 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:10O:3

Conservation

PhyloP100: 9.30

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, 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 id is 92467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80112072-G-A is described in Lovd as [Benign]. Variant chr17-80112072-G-A is described in Lovd as [Benign]. Variant chr17-80112072-G-A is described in Lovd as [Likely_benign].

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 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 12 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 12 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00907

AC:

1380

AN:

152194

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0177

AC:

4439

AN:

251298

Hom.:

230

AF XY:

0.0175

AC XY:

2382

AN XY:

135868

show subpopulations

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 SAS exome

AF:

0.0282

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.:

AF XY:

0.00885

AC XY:

6438

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00928

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.170

Gnomad4 SAS exome

AF:

0.0273

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.000943

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.00911

AC:

1387

AN:

152312

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

783

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.147

Gnomad4 SAS

AF:

0.0313

Gnomad4 FIN

AF:

0.0156

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00626

Hom.:

136

Bravo

AF:

0.00842

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000465

AC:

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:10Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:2Other:3

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. -

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. -

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

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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) -

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. -

not specified

Benign:3

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

- -

PreventionGenetics, part of Exact Sciences

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

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

.;D

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Uncertain

0.71

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

GERP RS

4.7

Varity_R

0.94

gMVP

0.93

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over