17-80113329-G-A

Position:

chr17-80113329-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS3_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2152G>A variant in GAA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 718 (p.Val718Ile). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00011 in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting. The highest minor allele frequency in any population is 0.005329 in the Ashkenazi Jewish population. This allele frequency meets the criteria for BS1 (>0.005) but BS1 was not applied because the Ashkenazi Jewish population is not defined as a continental population (PMID:30311383). When expressed in COS-7 cells, this variant does not result in significantly reduced GAA activity, and the gene product is normally synthesized and/or processed (PMID 22644586, 31228295) (BS3_Supporting). The computational predictor REVEL gives a score of 0.193 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281232) with four submitters classifying the variant as a variant of uncertain significance, four as likely benign and one 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: BP4, BS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815626/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:8

Conservation

PhyloP100: -1.41

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 -2 ACMG points.

BP4

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

BS3

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.2152G>A	p.Val718Ile	missense_variant	15/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2152G>A	p.Val718Ile	missense_variant	15/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000274

AC:

AN:

219060

Hom.:

AF XY:

0.000262

AC XY:

AN XY:

118390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

184

AN:

1443584

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

716036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00511

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.0000720

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.000403

GnomAD4 genome

AF:

0.000204

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val718Ile variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL, Illumina, and Invitae) and a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories) in ClinVar (Variation ID: 281232). This variant has been identified in 0.533% (51/9570) of Ashkenazi Jewish chromosomes, 0.011% (3/27108) of South Asian chromosomes and 0.007% (8/112166) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141017311). 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. In vitro functional studies provide some evidence that the p.Val718Ile variant may have no impact on GAA activity or protein levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. 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, 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 and well-established functional studies. ACMG/AMP Criteria applied: BS3, BS1, BP4 (Richards 2015). -
Likely benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 21, 2024	The NM_000152.5:c.2152G>A variant in GAA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 718 (p.Val718Ile). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00011 in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting. The highest minor allele frequency in any population is 0.005329 in the Ashkenazi Jewish population. This allele frequency meets the criteria for BS1 (>0.005) but BS1 was not applied because the Ashkenazi Jewish population is not defined as a continental population (PMID: 30311383). When expressed in COS-7 cells, this variant does not result in significantly reduced GAA activity, and the gene product is normally synthesized and/or processed (PMID 22644586, 31228295) (BS3_Supporting). The computational predictor REVEL gives a score of 0.193 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281232) with four submitters classifying the variant as a variant of uncertain significance, four as likely benign and one 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: BP4, BS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 19, 2017

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2019

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

0.077

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.64

DANN

Benign

0.80

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.74

.;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.99

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.19

Sift

Benign

0.35

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0080

B;B

Vest4

0.11

MVP

0.58

MPC

0.091

ClinPred

0.010

GERP RS

-3.1

Varity_R

0.058

gMVP

0.42

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