rs113085339

Positions:

chr17-80105878-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA198772/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0019 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 3 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:11

Conservation

PhyloP100: 0.663

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 Likely_benign. Variant got -5 ACMG points.

BP4

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.676C>G	p.Leu226Val	missense_variant	3/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.676C>G	p.Leu226Val	missense_variant	3/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

272

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00576

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000594

AC:

144

AN:

242408

Hom.:

AF XY:

0.000553

AC XY:

AN XY:

132086

show subpopulations

Gnomad AFR exome

AF:

0.00666

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000277

AC:

400

AN:

1445942

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

220

AN XY:

718546

show subpopulations

Gnomad4 AFR exome

AF:

0.00740

Gnomad4 AMR exome

AF:

0.000695

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000659

Gnomad4 OTH exome

AF:

0.000683

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152368

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00623

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000541

Hom.:

Bravo

AF:

0.00198

ESP6500AA

AF:

0.00568

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000692

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 13, 2019	- -
Likely benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Leu226Val variant in GAA has not been reported in an individual with Glycogen Storage Disease II but has been reported in 1 European individual with unexplained limb-girdle muscle weakness (PMID: 29149851), and has been reported as a likely benign variant by EGL Genetic Diagnostics, GeneDx, and Invitae in ClinVar (Variation ID: 188476). This variant has been identified in 0.6298% (156/24770) of African chromosomes, 0.0622% (22/35358) of Latino chromosomes, and 0.0126% (16/127350) of European (non-Finnish) chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113085339). This variant has been seen in the general population at a greater frequency than expected for Glycogen Storage Disease II and is consistent with a benign role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 07, 2024	The NM_000152.5:c.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2023	Variant summary: GAA c.676C>G (p.Leu226Val) results in a conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 242408 control chromosomes (1 homozygote), predominantly at a frequency of 0.0067 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.676C>G has been reported in the literature in an individual affected limb-girdle muscular weakness with a non-informative genotype (Johnson_2017). The report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -

GAA-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular fibrillation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 20, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2019

This variant is associated with the following publications: (PMID: 29149851) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

This alteration is classified as likely 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

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.73

T;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.2

.;M;M

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.090

.;N;N

REVEL

Benign

0.16

Sift

Benign

0.39

.;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0090

.;B;B

Vest4

0.11

MVP

0.91

MPC

0.11

ClinPred

0.0081

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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