rs779556619

Positions:

chr17-80112001-T-C

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_SupportingPS3_ModeratePM3PP4_ModeratePP3

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

Scores

13

5

1

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 7.44

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 links:

GAA (HGNC:):

GAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1655T>C	p.Leu552Pro	missense_variant	12/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.1655T>C	p.Leu552Pro	missense_variant	12/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

5

AN:

152102

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

8

AN:

250910

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135734

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 SAS 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

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000342

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

5

AN:

152102

Hom.:

0

Cov.:

33

AF XY:

0.0000269

AC XY:

2

AN XY:

74300

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000558

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

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 02, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 07, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Aug 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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). 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 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. -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 20, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

GAA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

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

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.79

D

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

4.0

H;H

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

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.90

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

1.0

MPC

0.69

ClinPred

1.0

D

GERP RS

4.7

Varity_R

0.95

gMVP

0.98

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779556619; hg19: chr17-78085800;