17-80110793-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID:24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompedisease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815358/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

2
7
10

Clinical Significance

Uncertain significance reviewed by expert panel U:14

Conservation

PhyloP100: 4.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GAANM_000152.5 linkc.1504A>G p.Met502Val missense_variant Exon 10 of 20 ENST00000302262.8 NP_000143.2 P10253

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GAAENST00000302262.8 linkc.1504A>G p.Met502Val missense_variant Exon 10 of 20 1 NM_000152.5 ENSP00000305692.3 P10253

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152148
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000132
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251226
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.0000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000800
AC:
117
AN:
1461842
Hom.:
0
Cov.:
37
AF XY:
0.0000756
AC XY:
55
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.000103
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152148
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000957
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000327
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:14
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Uncertain:8
Aug 01, 2022
MGZ Medical Genetics Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the GAA protein (p.Met502Val). This variant is present in population databases (rs376067362, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 24158270, 33202836; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 439746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 21, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1504A>G (p.M502V) variant in the GAA gene has been reported in conjunction with another variant in an unaffected individual (PMID: 24158270) and in a newborn screen (PMID: 33202836). There is insufficient evidence at this time to determine the significance of this variant. -

Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 05, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 22, 2020
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

The heterozygous p.Met502Val variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 24158270). This variant has been identified in 0.010% (13/128968) of European (non-Finnish) chromosomes and 0.003% (1/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376067362). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by Invitae, EGL Genetic Diagnostics, Illumina, and ARUP Laboratories in ClinVar (Variation ID: 439746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Methionine (Met) at position 502 is not highly conserved in mammals and evolutionary distant species, and one species (American alligator) carries a Valine (Val), raising the possibility that this change at this position may be tolerated. This variant was reported in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II (PMID: 24158270). In summary, the clinical significance of the p.Met502Val variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -

Oct 01, 2023
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID: 24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023). -

not provided Uncertain:4
Apr 13, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 07, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 28, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed with a second variant in GAA in a patient with late-onset Pompe disease; the phase of these variants was not determined (PMID: 24158270); Observed with additional variants in GAA in a patient with low GAA activity on newborn screening (PMID: 33202836); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 22253258, 19343043, 30985853, 24158270, 33202836) -

Jul 16, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2, PM3 -

not specified Uncertain:2
Oct 12, 2016
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 09, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GAA c.1504A>G (p.Met502Val) results in a conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251226 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.1504A>G has been reported in the literature in at least 2 individuals affected with or positive on a newborn screen for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Remiche_2014, Ficicioglu_2020). However, 2 unaffected individuals have been reported carrying this variant in trans with a pathogenic variant or pathogenic allele (c.-32-13T>G per Pompe disease variant database; [c.-32-13T>G;c.1856G>A] per ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect in patient cells results in 10%-<30% of normal activity (example, Remiche_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33202836, 24158270). ClinVar contains an entry for this variant (Variation ID: 439746). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.019
T
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Uncertain
0.75
D;D
Eigen
Benign
-0.021
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.73
.;T
M_CAP
Pathogenic
0.38
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Uncertain
0.035
D
MutationAssessor
Benign
1.7
L;L
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Pathogenic
0.81
Sift
Benign
0.51
T;T
Sift4G
Benign
0.51
T;T
Polyphen
0.16
B;B
Vest4
0.31
MVP
0.95
MPC
0.20
ClinPred
0.11
T
GERP RS
5.4
Varity_R
0.77
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs376067362; hg19: chr17-78084592; API