17-80108724-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePM3PS3_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1222A>G variant in GAA is predicted to result in the substitution of methionine by valine at amino acid 408 (p.Met408Val). Four patients have been reported with this variant; three with infantile onset Pompe disease and documented values showing GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID:11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID:21687968) (PP4_Moderate). One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del, confirmed in trans (PMID:34995642) (ClinVar Variation ID: 952947). Another patient is homozygous for the variant (PMID:26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID:21687968) or c.1408_1410del (PMID:11738358); the allelic data for these two patients will be used in the classification of the other variant and is not included here to avoid circular logic (PM3). When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 26, 2020. Since then, the data for this variant have been re-evaluated. The classification of likely pathogenic was reapproved on May 6, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815236/MONDO:0009290/010

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 2.56

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 Likely_pathogenic. Variant got 6 ACMG points.

PS3

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

PM2

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

PM3

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

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.1222A>G	p.Met408Val	missense_variant	Exon 8 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.1222A>G	p.Met408Val	missense_variant	Exon 8 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248202

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1460294

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:6

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met408Val variant in GAA has been reported in 5 individuals (including 2 Spanish, 2 from the UK, and 1 Taiwanese) with Glycogen Storage Disease II (PMID: 11738358, 21687968, 17616415, 26497565, 20080426), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 371235). This variant has been identified in 0.002% (2/111716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs560575383). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Met408Val variant may impact GAA activity (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Methionine (Met) at position 408 is not conserved in evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Met408Val variant is pathogenic (PMID: 26497565). The phenotype of an individual homozygous and 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormal GAA activity assay results in relevant tissues (PMID: 26497565, 17616415, 11738358). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP4, PM3_Supporting (Richards 2015). -

Nov 01, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1222A>G (p.Met408Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248202 control chromosomes (gnomAD). c.1222A>G has been reported in the literature in homozygous or compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Fernandez-Hojas_2002, Gort_2007, Labrousse_2010, Manwaring_2012, Broomfield_2016). These data indicate that the variant is likely to be associated with disease. The variant protein was reported to have less than 2% GAA activity in an in vitro expression system (Flanagan_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 03, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAA c.1222A>G variant is classified as Likely Pathogenic (PM2_Supporting, PS3, PM3-supporting, PP4_Moderate) The GAA c.1222A>G variant is a single nucleotide change in exon 8/20 of the GAA gene, which is predicted to change the amino acid methionine at position 408 in the protein to valine. This variant is absent from population databases (PM2_supporting). Functional studies show that the variant results in less than 2% of wild-type GAA activity (PMID:19862843) (PS3). This variant has been detected as homozygous and compound heterozygous in affected patients (PMID:26497565, 11738358) (PM3_supporting). The clinical features of this case are highly specific for a variant in the GAA gene (PP4_moderate). The variant has been reported in dbSNP (rs560575383) and in the HGMD database (CM020004). It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 371235). -

Sep 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. ClinVar contains an entry for this variant (Variation ID: 371235). This missense change has been observed in individual(s) with Pompe disease (PMID: 11738358, 21687968). This variant is present in population databases (rs560575383, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 408 of the GAA protein (p.Met408Val). -

May 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1222A>G variant in GAA is predicted to result in the substitution of methionine by valine at amino acid 408 (p.Met408Val). Four patients have been reported with this variant; three with infantile onset Pompe disease and documented values showing GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID: 11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID: 21687968) (PP4_Moderate). One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del, confirmed in trans (PMID: 34995642) (ClinVar Variation ID: 952947). Another patient is homozygous for the variant (PMID: 26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID: 21687968) or c.1408_1410del (PMID: 11738358); the allelic data for these two patients will be used in the classification of the other variant and is not included here to avoid circular logic (PM3). When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 26, 2020. Since then, the data for this variant have been re-evaluated. The classification of likely pathogenic was reapproved on May 6, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting. -

not provided

Pathogenic:1

Jul 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the apparently homozygous state and with a second GAA variant in patients with infantile-onset Pompe disease in published literature (PMID: 11738358, 17616415, 21687968, 26497565); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as p.(M408V) had less than 2% wildtype GAA activity in transfected cells (PMID: 19862843); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 19343043, 22253258, 30281819, 11738358, 31254424, 17616415, 20157781, 34995642, 19862843, 21687968, 26497565, 20080426) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.3

H;H

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.99

D;D

Vest4

0.63

MVP

0.99

MPC

0.52

ClinPred

0.93

GERP RS

4.4

Varity_R

0.79

gMVP

0.85

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