rs779556619

Variant names:

• chr17-80112001-T-C
• rs779556619
• NM_000152.5:c.1655T>C

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PS3_Moderate PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1655T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 552 (p.Leu552Pro). More than 10 individuals diagnosed with Pompe disease have been reported with this variant including at least 7 probands for whom laboratory data is published showing GAA activity in the deficient range (PMID 12923862, 18285536, 25681614, 27666774)(PP4_Moderate). Eight of these individuals were compound heterozygous for the variant and a pathogenic variant, phase unknown in all cases (PMID 12923862, 18285536, 18607768, 20033296, 25681614, 29122469 29422078, and two individuals were homozygotes (PMID 27666774)(PM3_Very strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In two functional studies, this variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 14695532, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with nine submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3.(Classification approved August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815429/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 7.44
• Publications: 43 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 8 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.
• 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	c.1655T>C	p.Leu552Pro	missense_variant	Exon 12 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1655T>C	p.Leu552Pro	missense_variant	Exon 12 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 33

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250910 AF XY: 0.0000147

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: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461506 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111890

Other (OTH) AF: 0.0000497 AC: 3 AN: 60382

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000827 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:11 Other:1

Aug 03, 2023

KardioGenetik, Herz- und Diabeteszentrum NRW

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 08-27-2021 by PerkinElmer Genomics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 552 of the GAA protein (p.Leu552Pro). This variant is present in population databases (rs779556619, gnomAD 0.006%). This missense change has been observed in individuals with Pompe disease (PMID: 14695532, 17616415, 18607768, 19588081, 20638881, 24158270, 25681614, 27666774). ClinVar contains an entry for this variant (Variation ID: 279811). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 17213836, 19862843, 25036864, 25409744). For these reasons, this variant has been classified as Pathogenic.

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Jul 19, 2016

Counsyl

Significance: 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 07, 2021

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5: c.1655T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 552 (p.Leu552Pro). More than 10 individuals diagnosed with Pompe disease have been reported with this variant including at least 7 probands for whom laboratory data is published showing GAA activity in the deficient range (PMID 12923862, 18285536, 25681614, 27666774)(PP4_Moderate). Eight of these individuals were compound heterozygous for the variant and a pathogenic variant, phase unknown in all cases (PMID 12923862, 18285536, 18607768, 20033296, 25681614, 29122469 29422078, and two individuals were homozygotes (PMID 27666774)(PM3_Very strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting. In two functional studies, this variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 14695532, 19862843)(PS3_Moderate). The computational predictor REVEL gives a score of 0.94, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with nine submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3_Very Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3. (Classification approved August 17, 2021)

Jan 22, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu552Pro variant in GAA has been reported in 26 individuals (including 5 Italian, 5 Brazilian, 4 German, 2 Spanish, and 2 Greek individuals) with Glycogen Storage Disease II, segregated with disease in 6 affected relatives from 3 families (PMID: 12923862, 19862843, 12213618, 22658377, 16838077, 18285536, 25681614, 16917947, 14695532, 17616415, 18607768, 19588081, 24158270, 23160972), and has also been reported pathogenic (by GeneDx, EGL, Counsyl, and Integrated Genetics/Laboratory Corporation of America) in ClinVar (Variation ID: 279811). This variant has been identified in 0.007% (8/111590) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779556619). 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.Leu552Pro variant may impact GAA processing, levels, and activity (PMID: 14695532, 19862843). However, these types of assays may not accurately represent biological function. 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 presence of this variant in combination with reported pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu552Pro variant is pathogenic (PMID: 12923862, 12213618, 16838077, 18285536, 25681614, 16917947, 24158270; Variation ID: 371622, 550327, 550355). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with <10% GAA activity detected in their muscle, lymphocyte, and muscle cells (PMID: 16917947, 12213618, 20033296, 12923862, 27666774, 19046416, 16838077, 24158270, 25681614, 18285536). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with likely pathogenic and pathogenic variants in Glycogen Storage Disease II and in vitro functional studies with COS cells transfected with this variant. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015).

Sep 02, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.1655T>C (p.Leu552Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120282 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant has been identified in many Pompe patients in the literature in homozygous and compound heterozygous state. In at least one patient with a compound heterozygous genotype, leukocyte GAA enzyme residual activity was 18.78% of normal, indicating that this variant has significantly reduced activity. Taken together, this variant is classified as pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 02, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:7

Sep 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple unrelated individuals with Pompe disease in published literature (PMID: 12213618, 22658377, 24158270); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the p.(L552P) variant resulted in significantly reduced enzyme activity compared to wildtype and transfected cells failed to localize to lysosomes (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: 11949932, 22658377, 27862019, 25681614, 14695532, 18285536, 34530085, 31254424, 24158270, 22990675, 25036864, 23668440, 27666774, 25052852, 19588081, 16917947, 18607768, 29422078, 31086307, 34426522, 33560568, 33202836, 36246652, 37937776, 34852371, 25687635, 19862843, 12213618)

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 26, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 20, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 26, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

GAA-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GAA c.1655T>C variant is predicted to result in the amino acid substitution p.Leu552Pro. This variant was reported in over 40 individuals with glycogen storage disease 2 (for example: Flanagan et al. 2009. PubMed ID: 19862843; Ünve et al. 2016. PubMed ID: 27666774; Parini et al. 2018. PubMed ID: 29422078; Kishnani et al. 2019. PubMed ID: 31086307; de Faria et al. 2020. PubMed ID: 33560568). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		7.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.97
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.98
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779556619; hg19: chr17-78085800;