rs145866792

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.688G>A variant in GAA is a missense variant predicted to result in the substitution of valine by methionine at amino acid 230 (p.Val230Met). The highest population minor allele frequency in gnomAD v2.1.1. is 0.002261 (56/24772 alleles) in the African/African American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.482 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 196222). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA207869/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:10B:1

Conservation

PhyloP100: 6.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.688G>A	p.Val230Met	missense_variant	3/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.688G>A	p.Val230Met	missense_variant	3/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000225

AC:

AN:

240460

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

131096

show subpopulations

Gnomad AFR exome

AF:

0.00249

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000723

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1442352

Hom.:

Cov.:

AF XY:

0.0000516

AC XY:

AN XY:

716506

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000551

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000357

Hom.:

Bravo

AF:

0.000650

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 06, 2018	Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Val230Met (c.688G>A) in exon 3 of the GAA gene (NM_000152.3) Chromosome location 17-78079689-G-A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS). This variant has not been reported in the literature in association with disease, according to the Invitae report. Of note: The GAA gene is associated with autosomal recessive glycogen storage disease type II (GSDII), also known as Pompe disease (MedGen UID: 5340). Our adult patient does not display any known clinical symptoms of Pompe, and because this is a recessive condition she would need to have a disease-causing variant in each allele in order to have the condition. This one variant in one allele would not be sufficient, even if it were pathogenic. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is highly conserved across ~100 vertebrate species for which we have data. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant was reported in 74 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.03%. It is most prevalent among individuals with either African or Latino ancestry (like our patient). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 9425285, 7603530, 19343043, 22253258) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 08, 2019	- -

Glycogen storage disease, type II

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 13, 2023	The NM_000152.5:c.688G>A variant in GAA is a missense variant predicted to result in the substitution of valine by methionine at amino acid 230 (p.Val230Met). The highest population minor allele frequency in gnomAD v2.1.1. is 0.002261 (56/24772 alleles) in the African/African American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.482 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 196222). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 09, 2015

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2015

The p.V230M variant (also known as c.688G>A), located in coding exon 2 of the GAA gene, results from a G to A substitution at nucleotide position 688. The valine at codon 230 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

4.0

.;H;H

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

.;N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0050

.;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.69

MVP

0.95

MPC

0.48

ClinPred

0.18

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.78

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

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