17-80110767-C-T

Position:

chr17-80110767-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_SupportingPM3_StrongPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1478C>T variant in GAA is predicted to result in the substitution of proline by leucine at amino acid 493 (p.Pro493Leu). At least 7 probands have been reported with this variant, including one adult and an affected sibling with documented values showing GAA activity below the normal range on dried blood spot assay, and treated with enzyme replacement therapy (ERT) (PMID 24495340), and another four individuals with features consistent with Pompe disease, three of them on enzyme replacement therapy (PMID:25455803, 29181627, 31545528, 33188503). Furthermore, three individuals with the same genotype (thought to be unrelated but cannot be confirmed) were identified in a clinical diagnostic laboratory with GAA activity below the normal range on dried blood spot (PP4_Moderate). Two additional patients have been reported with P493L, but the cDNA change was not provided and, one patient was heterozygous without the identification of a second variant, therefore, this data will not be included (PMID:20033296, 23160972, 31545528), and patient with suspected late onset Pompe disease was identified by newborn screening but was asymptomatic (PMID:33202836). The 7 probands are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all of these patients. The second variant is either c.525delT (PMID:25455803, and 3 presumably unrelated patients identified by a clinical diagnostic laboratory, max 2 patients counted, ClinVar Variation ID: 4033, SCV001443331.1; 2 x 0.5 points), c.1134C>G (p.Tyr378Ter), phase unknown (PMID:29181627, ClinVar Variation ID: 595469, SCV001443283.2, 0.5 points), c.307T>G (p.Cys103Gly) (PMID:24495340, ClinVar Variation ID: 92483, SCV002817442.1, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1, 0.5 points), c.1655T>C (p.Leu552Pro) (PMID:31545528, ClinVar Variation ID: 279811, SCV001371750.2) or c.-32-13T>G (PMID:33188503, ClinVar Variation ID: 4027). 7 x 0.5 points = 3.5 points (PM3_Strong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003 (4/128962 alleles) in the European non-Finnish population, and in gnomAD v4.1. the MAF is 0.00001695 (20/1180038) in the European non-Finnish population. Both are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.911 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, results of functional studies are not available for this variant. There is a ClinVar entry for this variant (Variation ID 379593). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 21, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608675/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:1

Conservation

PhyloP100: 5.70

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 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.

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.1478C>T	p.Pro493Leu	missense_variant	10/20	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.1478C>T	p.Pro493Leu	missense_variant	10/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152186

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251208

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135872

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727230

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

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:

0.0000370

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000152.3(GAA):c.1478C>T(P493L) is a missense variant classified as likely pathogenic in the context of Pompe disease. P493L has been observed in cases with relevant disease (PMID: 25455803, 5614309, 29181627, 29653542). Functional assessments of this variant are not available in the literature. P493L has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, NM_000152.3(GAA):c.1478C>T(P493L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 27, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jul 21, 2024	The NM_000152.5:c.1478C>T variant in GAA is predicted to result in the substitution of proline by leucine at amino acid 493 (p.Pro493Leu). At least 7 probands have been reported with this variant, including one adult and an affected sibling with documented values showing GAA activity below the normal range on dried blood spot assay, and treated with enzyme replacement therapy (ERT) (PMID 24495340), and another four individuals with features consistent with Pompe disease, three of them on enzyme replacement therapy (PMID: 25455803, 29181627, 31545528, 33188503). Furthermore, three individuals with the same genotype (thought to be unrelated but cannot be confirmed) were identified in a clinical diagnostic laboratory with GAA activity below the normal range on dried blood spot (PP4_Moderate). Two additional patients have been reported with P493L, but the cDNA change was not provided and, one patient was heterozygous without the identification of a second variant, therefore, this data will not be included (PMID: 20033296, 23160972, 31545528), and patient with suspected late onset Pompe disease was identified by newborn screening but was asymptomatic (PMID: 33202836). The 7 probands are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. The phase is unconfirmed in all of these patients. The second variant is either c.525delT (PMID: 25455803, and 3 presumably unrelated patients identified by a clinical diagnostic laboratory, max 2 patients counted, ClinVar Variation ID: 4033, SCV001443331.1; 2 x 0.5 points), c.1134C>G (p.Tyr378Ter), phase unknown (PMID: 29181627, ClinVar Variation ID: 595469, SCV001443283.2, 0.5 points), c.307T>G (p.Cys103Gly) (PMID: 24495340, ClinVar Variation ID: 92483, SCV002817442.1, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1, 0.5 points), c.1655T>C (p.Leu552Pro) (PMID: 31545528, ClinVar Variation ID: 279811, SCV001371750.2) or c.-32-13T>G (PMID: 33188503, ClinVar Variation ID: 4027). 7 x 0.5 points = 3.5 points (PM3_Strong). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00003 (4/128962 alleles) in the European non-Finnish population, and in gnomAD v4.1. the MAF is 0.00001695 (20/1180038) in the European non-Finnish population. Both are lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.911 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, results of functional studies are not available for this variant. There is a ClinVar entry for this variant (Variation ID 379593). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 21, 2024) -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Pro493Leu variant in GAA has been reported in 6 individuals from Germany or Austria with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 29181627, 24495340, 23160972, 20033296, 25455803), and has also been reported likely pathogenic by GeneDx and Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 379593). This variant has been identified in 0.003% (4/128962) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148842275). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Pro493Leu variant is pathogenic (PMID: 20033296, 24495340). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in dried blood spots, consistent with disease (PMID: 20033296, 24495340). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4, PM3_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 493 of the GAA protein (p.Pro493Leu). This variant is present in population databases (rs148842275, gnomAD 0.003%). This missense change has been observed in individual(s) with reduced Œ±-glucosidase acitivity (PMID: 20033296, 24495340, 25455803, 29181627). ClinVar contains an entry for this variant (Variation ID: 379593). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 11, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24495340, 25455803, 20033296, 33202836, 27896092, 33188503, 29181627) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

.;T

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.026

D;D

Polyphen

0.97

D;D

Vest4

0.94

MVP

1.0

MPC

0.51

ClinPred

1.0

GERP RS

5.5

Varity_R

0.70

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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