chr17-80112664-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3PM2_SupportingPM5PM3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1841C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 614 (p.Thr614Met). At least 2 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PP4_Moderate). This variant has been detected in at least 3 individuals with Pompe disease. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (PMID:33741225). At least 2 individuals were homozygous for the variant (PMID:33301762, 33741225, 33250842) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004184 (1/23902 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.769 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5). Splicing prediction using Splice AI revealed no expected effects on splicing due to either of these variants. There is a ClinVar entry for this variant (Variation ID: 286469, 1 star review status) with 3 submitters classifying the variant as uncertain significance, 2 submitters as likely pathogenic, and 1 submitter as pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_Moderate, PP3, PM3, PM5, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815496/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:10U:3

Conservation

PhyloP100: 3.27

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease II
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
glycogen storage disease due to acid maltase deficiency, infantile onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
glycogen storage disease due to acid maltase deficiency, late-onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

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

PM3

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.

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.1841C>T	p.Thr614Met	missense_variant	Exon 13 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.1841C>T	p.Thr614Met	missense_variant	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00000817

AC:

AN:

244678

AF XY:

0.00000749

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460012

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726272

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111722

Other (OTH)

AF:

0.0000166

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:8

Mar 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GAA c.1841C>T; p.Thr614Met variant (rs369531647) is reported in the literature in multiple individuals affected with Pompe disease, one individual carried a second GAA variant, and several individuals were homozygous for p.Thr614Met (Chakravorty 2020, Puri 2021, Thomas 2021). This variant is also reported in ClinVar (Variation ID: 286469). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1841C>A, p.Thr614Lys) have been reported in individuals with Pompe disease and are considered pathogenic (Kroos 2008, Reddy 2017). Computational analyses predict that this variant is deleterious (REVEL: 0.769). Based on available information, this variant is considered to be likely pathogenic. References: Chakravorty S et al. Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. Front Neurol. 2020 Nov 5;11:559327. PMID: 33250842. Kroos M et al. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745. PMID: 18425781. Puri RD et al. Late onset Pompe Disease in India - Beyond the Caucasian phenotype. Neuromuscul Disord. 2021 May;31(5):431-441. PMID: 33741225. Reddy HM et al. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2017 Feb;62(2):243-252. PMID: 27708273. Thomas DC et al. Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease. Clin Biochem. 2021 Mar;89:14-37. PMID: 33301762. -

Feb 24, 2025

Department of Human Genetics, Hannover Medical School

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: PM2_Supporting, PM3, PM5, PP3, PP4_Moderate -

Oct 15, 2020

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant c.1841C>T has been reported by Nallamilli et. al. 2018 PMID:30564623 -

Jul 22, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2022

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.1841C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 614 (p.Thr614Met). At least 2 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes (PP4_Moderate). This variant has been detected in at least 3 individuals with Pompe disease. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant (PMID: 33741225). At least 2 individuals were homozygous for the variant (PMID: 33301762, 33741225, 33250842) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004184 (1/23902 alleles) in the African/African-American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.769 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113), in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5). Splicing prediction using Splice AI revealed no expected effects on splicing due to either of these variants. There is a ClinVar entry for this variant (Variation ID: 286469, 1 star review status) with 3 submitters classifying the variant as uncertain significance, 2 submitters as likely pathogenic, and 1 submitter as pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP4_Moderate, PP3, PM3, PM5, PM2_Supporting -

Mar 21, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GAA c.1841C>T (p.Thr614Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244678 control chromosomes. c.1841C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, Chakravorty_2020, Puri_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Puri_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 614 of the GAA protein (p.Thr614Met). This variant is present in population databases (rs369531647, gnomAD 0.003%). This missense change has been observed in individuals with late onset Pompe disease (PMID: 33250842, 33741225). ClinVar contains an entry for this variant (Variation ID: 286469). 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.Thr614 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21484825, 24513544, 24590251, 27708273). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:3

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 33301762, 19343043, 22253258, 33250842, 38444573, 33741225, 38250073) -

Oct 21, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rare genetic deafness

Pathogenic:1

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr614Met variant in GAA has been previously reported in reported in three glycogen storage disease II (GSD2 aka Pompe disease) patients (Chakravorty 2020 PMID: 33250842, Puri 2021 PMID: 33741225), two of whom were homozygous for the variant and one was compound heterozygous with a loss of function variant. The variant was present in 0.01% (5/41458) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitue.org); however this frequency is low enough to be consistent with a recessive allele frequency. The variant has also been reported in ClinVar (ClinVar ID 286469). In vitro studies from whole blood leukocytes of patients with the variants indicate that the variant impacts enzyme activity (Puri 2021 PMID: 33741225). In addition, computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Thr614Lys) has been reported as pathogenic by the ClinGen Lysosomal Storage Variant Curation Expert Panel (ClinVar ID 167113). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycogen storage disease II. ACMG/AMP Criteria applied: PM3_S, PM5, PP3, PS3_P. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

3.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

N;N

REVEL

Pathogenic

0.77

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.89

Gain of MoRF binding (P = 0.0772);Gain of MoRF binding (P = 0.0772);

MVP

1.0

MPC

0.55

ClinPred

0.94

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.88

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over