17-80110953-C-T

Position:

chr17-80110953-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_ModeratePM2_SupportingPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1564C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 522 (p.Pro522Ser). Two probands with a confirmed diagnosis of IOPD have been reported with this variant (PMID:32518148, 38250073), both CRIM-positive, one with documented symptoms of IOPD and the other on ERT (PP4_Moderate). Both probands are compound heterozygotes for the variant and other variants that have yet to be classified by the ClinGen Lysosomal Diseases VCEP (PM3_Not Met). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001761 in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe"). This includes 0.8% GAA activity in cells and 0.8% in medium, and evidence of abnormal synthesis and processing on Western blot (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.932 which is higher than the ClinGen LD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 972746). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PS3_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294895008/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 6.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.

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.1564C>T	p.Pro522Ser	missense_variant	11/20	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.1564C>T	p.Pro522Ser	missense_variant	11/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251280

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727104

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: GAA c.1564C>T (p.Pro522Ser) 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 8e-06 in 251280 control chromosomes. c.1564C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, e.g. Kroos_2008, Kishnani_2019, Reuser_2019, De Groot_2021). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Kroos_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 19, 2024	The NM_000152.5:c.1564C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 522 (p.Pro522Ser). Two probands with a confirmed diagnosis of IOPD have been reported with this variant (PMID: 32518148, 38250073), both CRIM-positive, one with documented symptoms of IOPD and the other on ERT (PP4_Moderate). Both probands are compound heterozygotes for the variant and other variants that have yet to be classified by the ClinGen Lysosomal Diseases VCEP (PM3_Not Met). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00001761 in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2, meeting this criterion. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe"). This includes 0.8% GAA activity in cells and 0.8% in medium, and evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.932 which is higher than the ClinGen LD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. There is a ClinVar entry for this variant (Variation ID: 972746). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: PP4_Moderate, PS3_Moderate, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Pro522Ser variant in GAA has been reported in one individual with glycogen storage disease II (PMID: 18425781) and has been identified in 0.002% (2/113602) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs892129065). 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 using COS cells transfected with the variant provide some evidence that the p.Pro522Ser variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro522Thr and p.Pro522Ala, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 44946, 371277). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 15, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 23, 2023	ClinVar contains an entry for this variant (Variation ID: 972746). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 522 of the GAA protein (p.Pro522Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed on the same chromosome as p.Tyr766Asn in individual(s) with Pompe disease (PMID: 31086307). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). This variant disrupts the p.Pro522 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17643989, 18429042, 26800218, 29422078). 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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	Published functional studies demonstrate reduced enzyme activity in COS-7 and HEK-293 cells (PMID: 22644586); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31086307, 18425781, 29422078, 22644586) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.011

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.96

Gain of disorder (P = 0.0806);Gain of disorder (P = 0.0806);

MVP

1.0

MPC

0.54

ClinPred

1.0

GERP RS

5.5

Varity_R

0.96

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over