17-80110020-A-T

Position:

chr17-80110020-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPP4_ModeratePM3PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1402A>T variant in GAA is a missense variant predicted tocause substitution of isoleucine by phenylalanine at amino acid 468 (p.Ile468Phe). This variant has been identified in at least four unrelated individuals described as having Pompe disease, including two patients with LOPD receiving ERT (PMID:37701327, 25037089). One of these patients has documented deficiency of GAA in DBS. One individual is part of a cohort of patients with LOPD receiving ERT, although GAA enzyme is not reported (PMID:37701327). This meets criteria for PP4_moderate. This variant has been reported in compound heterozygosity (phase unknown) in three unrelated patients with the common splice site variant c.-32-13T>G, meeting criteria for PM3. It has also been reported in one individual with confirmed deficient GAA in DBS, muscle, and skin fibroblast with no second variant reported on sequencing or deletion/duplication analysis (PMID:25037089). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002 (1/59986 alleles) in the Admixed American population, which is 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 0.747, which meets the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 269826), 1-star review status) with 9 submitters classifying the variant as likely pathogenic (1) and uncertain significance (8). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605170/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:7

Conservation

PhyloP100: 4.80

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.

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.1402A>T	p.Ile468Phe	missense_variant	9/20	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.1402A>T	p.Ile468Phe	missense_variant	9/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460956

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

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:

0.0000564

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:3Uncertain:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 468 of the GAA protein (p.Ile468Phe). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Pompe disease (PMID: 25037089, 30564623, 31086307, 31342611). ClinVar contains an entry for this variant (Variation ID: 285589). 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. 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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 19, 2023	The NM_000152.5:c.1402A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 468 (p.Ile468Phe). This variant has been identified in at least four unrelated individuals described as having Pompe disease, including two patients with LOPD receiving ERT (PMID: 37701327, 25037089). One of these patients has documented deficiency of GAA in DBS. One individual is part of a cohort of patients with LOPD receiving ERT, although GAA enzyme is not reported (PMID: 37701327). This meets criteria for PP4_moderate. This variant has been reported in compound heterozygosity (phase unknown) in three unrelated patients with the common splice site variant c.-32-13T>G, meeting criteria for PM3. It has also been reported in one individual with confirmed deficient GAA in DBS, muscle, and skin fibroblast with no second variant reported on sequencing or deletion/duplication analysis (PMID: 25037089). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00002 (1/59986 alleles) in the Admixed American population, which is 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 0.747, which meets the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 269826), 1-star review status) with 9 submitters classifying the variant as likely pathogenic (1) and uncertain significance (8). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PP4_moderate, PM3, PM2_supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2023). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 15, 2020	The p.Ile468Phe variant in GAA has been reported in two individuals with glycogen storage disease II (PMID: 25037089) and has been identified in 0.013% (2/15414) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043148). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Counsyl and EGL Genetic Diagnostics (VariationID: 285589). 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 phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 25037089). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 25037089) and in an individual with glycogen storage disease II increases the likelihood that the p.Ile468Phe variant is pathogenic. 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, PM3_supporting, PP4 (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2018	- -

not provided

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25037089, 30564623, 31086307) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.96

D;D

Vest4

0.93

MutPred

0.77

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

1.0

MPC

0.67

ClinPred

0.99

GERP RS

4.3

Varity_R

0.93

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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