17-80117015-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM5

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2237G>T variant in GAA is a missense variant predicted to cause substitution of tryptophan by leucine at amino acid 746 (p.Trp746Leu). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001102 (7/63508 alleles) in the European Finnish population, which is lower than the ClinGen Lysosomal Diseases threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.832 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.2238G>C, p.Trp746Cys) (ClinVar Variation ID 265160) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). Three additional different missense variants (c.2237G>C, p.Trp746Ser; c.2236T>C, p.Trp746Arg; and c.2236T>G, p.Trp746Gly), in the same codon have been reported in patients with Pompe disease (ClinVar Variation IDs 188484, 499293, 556431). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP. There is a ClinVar entry for this variant (Variation ID: 284776). In summary, there is currently insufficient evidence to determine the pathogenicity of this variant, and it meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM5, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815663/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

9
5
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 9.45
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 4 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
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.2237G>T p.Trp746Leu missense_variant Exon 16 of 20 ENST00000302262.8 NP_000143.2 P10253

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GAAENST00000302262.8 linkc.2237G>T p.Trp746Leu missense_variant Exon 16 of 20 1 NM_000152.5 ENSP00000305692.3 P10253

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152180
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:
0.000414
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000718
AC:
18
AN:
250744
Hom.:
0
AF XY:
0.0000884
AC XY:
12
AN XY:
135734
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000664
AC:
97
AN:
1461216
Hom.:
0
Cov.:
30
AF XY:
0.0000729
AC XY:
53
AN XY:
726926
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.000113
Gnomad4 NFE exome
AF:
0.0000702
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152298
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
8
AN XY:
74466
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:
0.000414
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000405
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:1Uncertain:3
Sep 05, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 746 of the GAA protein (p.Trp746Leu). This variant is present in population databases (rs752921215, gnomAD 0.01%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 23430949). ClinVar contains an entry for this variant (Variation ID: 284776). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7981676, 9535769, 21232767, 21757382, 25093132, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Oct 07, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 28, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2
Feb 28, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 16, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.92
D;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Benign
0.69
N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-12
D;D
REVEL
Pathogenic
0.83
Sift
Benign
0.039
D;D
Sift4G
Benign
0.099
T;T
Polyphen
0.99
D;D
Vest4
0.90
MVP
0.94
MPC
0.67
ClinPred
0.75
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.81

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.

Other links and lift over

dbSNP: rs752921215; hg19: chr17-78090814; API