17-80107616-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PP2PP5BP4

The NM_000152.5(GAA):c.752C>T(p.Ser251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S251W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:6

Conservation

PhyloP100: 2.56

Publications

32 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: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000152.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.

PP5

Variant 17-80107616-C-T is Pathogenic according to our data. Variant chr17-80107616-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 325781.

BP4

Computational evidence support a benign effect (MetaRNN=0.017314643). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000350

AC:

AN:

251126

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00283

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1460908

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00267

AC:

106

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00101

AC:

AN:

52622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111884

Other (OTH)

AF:

0.0000497

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000171

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000146

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:5Uncertain:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2019

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 251 of the GAA protein (p.Ser251Leu). This variant is present in population databases (rs200856561, gnomAD 0.3%). The c.752C>T (p.Ser251Leu) variant frequently co-occurs with the c.761C>T (p.Ser254Leu) variant (rs577915581) in cis (on the same chromosome), which is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the literature as homozygous or in combination with other GAA variants in multiple individuals affected with Pompe disease (PMID: 24513544, 29124014, 27183828). The clinical significance of the c.752C>T variant alone is unclear and has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 325781). 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 not expected to disrupt GAA protein function. While the c.752C>T (p.Ser251Leu) variant alone has not been shown to affect GAA protein function, the c.[752C>T; 761C>T] haplotype has been reported to reduce enzyme activity (PMID: 22644586). 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 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.Ser251Leu; p.Ser254Leu] complex variant in GAA has been reported in at least 15 individuals with Glycogen Storage Disease II (PMID: 24513544, 21232767, 27183828, 20080426), and has also been reported likely pathogenic by Illumina, pathogenic by GeneDx, and likely benign by Invitae in ClinVar (Variation ID: 325781, 325782). This variant has been identified in <0.28% of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200856561). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Ser251Leu variant may impact protein function (PMID: 22644586). 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 presence of this variant in the homozygous state and with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Ser251Leu variant is pathogenic (PMID: 24513544, 21232767). The phenotype of homozygotes and heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays in relevant tissues and the absence of known pseudodeficiency alleles, consistent with disease (PMID: 24513544, 21232767). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP4_moderate, PM3 (Richards 2015). -

Jan 24, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 11, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.02%, East Asian: 0.28%). Predicted Consequence/Location: Complex Allele Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 22644586). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GAA-related disorder (PMID: 31637888, Clinvar: VCV001321358). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 21232767, 24513544, 29124014). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3Uncertain:1

Jan 28, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25466677, 29122469, 27183828, 18458862, 24513544, 29451150, 29124014, 30555256, 31637888, 31980526) -

Apr 14, 2025

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_moderate; PM3_very strong; PP4 The GAA c.[752C>T;761C>T] (p.[(Ser251Leu);(Ser254Leu)]) complex allele has been reported in at least eight patients with glycogen storage disease II (PMID: 29124014, 27183828, 21232767). Furthermore, functional studies have been performed to support the pathogenicity of this variant. Studies in HEK293 and COS7 cells showed GAA activity was significantly reduced compared to wild type (PMID 22644586). -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 19, 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.752C>T (p.Ser251Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) 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 0.00035 in 282488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00035 vs 0.0042), allowing no conclusion about variant significance. c.752C>T has been reported in the literature as a complex allele in cis with c.761C>T (p.Ser254Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports. These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del , p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014, Yue_2024). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31228295, 21232767, 22644586, 20080426, 24513544, 38186848). ClinVar contains an entry for this variant (Variation ID: 325781). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GAA-related disorder

Uncertain:1

Jun 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GAA c.752C>T variant is predicted to result in the amino acid substitution p.Ser251Leu. This variant has been reported in individuals with glycogen storage disease 2, also called Pompe Disease (Tang et al. 2020. PubMed ID: 33073007; Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828; Lee et al. 2019. PubMed ID: 31637888). This variant is reported in 0.28% of alleles in individuals of East Asian descent in gnomAD. The c.752C>T variant frequently occurs in cis with the c.761C>T (p.Ser254Leu) variant, and is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the homozygous or compound heterozygous state in multiple individuals with Pompe disease (Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828). Of note, the c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) haplotype has been reported to be in cis with the c.1411_1414delGAGA variant (Labrousse et al. 2009. PubMed ID: 20080426; Chien et al. 2014. PubMed ID: 25466677; Mori et al. 2017. PubMed ID: 29122469). The c.[752C>T;761C>T] haplotype has been reported to significantly reduce GAA enzyme activity to 1.7-3.3% of wild-type activity (Kroos M et al 2012. PubMed ID: 22644586). ClinVar classifications for the c.752C>T variant range from uncertain, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/), while one lab has classified the c.[752C>T;761C>T] haplotype as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1321358/). Although we suspect that this variant may be pathogenic, at this time the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.85

T;.;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

.;M;M

PhyloP100

2.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.58

.;N;N

REVEL

Benign

0.20

Sift

Benign

0.54

.;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.0040

.;B;B

Vest4

0.36

MVP

0.78

MPC

0.097

ClinPred

0.041

GERP RS

4.2

Varity_R

0.18

gMVP

0.69

Mutation Taster

=33/67

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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