17-80108495-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3PM2_SupportingPS3_ModeratePM3_StrongPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1082C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 361 (p.Pro361Leu). This variant has been reported in at least 13 individuals with clinical symptoms consistent with Pompe disease including 6 individuals with documented laboratory values showing deficiency of GAA activity below normal range in leukocytes or <1% activity in fibroblasts or another tissue, many of whom were also reported to be showing improvement on enzyme replacement therapy and/or had specific features reported for infantile onset Pompe disease including cardiomyopathy and motor delay (PMID:21484825, 25139343, 25526786, 26497565, 27344650, 31439017, 31915562) and another patient with features specific for infantile onset Pompe disease, on enzyme replacement therapy (PMID:30023291). Pseudodeficiency variants, c.1726G>A and c.2065G>A, were reported to be absent in at least one of these patients (PMID:25526786) (PP4_Moderate). Of the patients reported with this variant, four are compound heterozygous for the variant and another variant in GAA classified as pathogenic by the ClinGen LSD VCEP including c.784G>A (p.Glu262Lys) (PMID:31915562; confirmed in trans by parental DNA testing) and c.1933G>A (p.Asp645Asn) (PMID:26497565, 27344650; phase unknown), c.1935C>A (p.Asp645Glu) (PMID:31439017; phase unknown), and c.2238G>C (p.Trp746Cys) (PMID:35123860; phase unknown). In addition, two homozygotes have been reported (PMID:30023291, 31931849), one of whom was identified by next generation sequencing panel for limb girdle muscle weakness, and not counted due to no report of follow up enzyme studies to confirm diagnosis of Pompe disease (PMID:31931849) (PM3_Strong). Additional patients have been reported with the variant in compound heterozygosity with another variant including c.503G>C (p.Arg168Pro) (PMID:25526786), c.953T>C (p.Met318Thr) (PMID:25139343), c.1309C>T (p.Arg437Cys) (PMID:12601120, 27692865), c.1432G>A (p.Gly478Arg) (PMID:25213570), c.1979G>A (p.Arg660His) (PMID:21484825), and c.1551+1G>C (PMID:16917947). In these cases, the allelic data will be used in the assessment of the second variant and was not applied to PM3 here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells and GAA deficient fibroblasts, this variant resulted in <4% wild type GAA activity in three different studies (PMID:12601120, 19862843, 22644586) and showed evidence of abnormal synthesis and processing on Western blot (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at the same codon, c.1082C>A (p.Pro361Arg) has been reported (PMID:31076647). The classification of p.Pro163Leu will be used in the assessment of p.Pro361Arg and, therefore, PM5 is not applied here. There is a ClinVar entry for this variant (Variation ID: 403712, 2 star review status) with four submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815163/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 7.39

Publications

29 publications found

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 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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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 link	c.1082C>T	p.Pro361Leu	missense_variant	Exon 7 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.1082C>T	p.Pro361Leu	missense_variant	Exon 7 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249370

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460752

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000260

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:9

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GAA c.1082C>T (p.Pro361Leu) 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 1.2e-05 in 249370 control chromosomes. c.1082C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. Eight 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 06, 2016

Claritas Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1082C>T (p.Pro361Leu) missense variant is previously reported in the literature and is expected to be causative of disease. This variant has been reported in multiple affected individuals across multiple studies. This variant is classified as Class B, which means potentially less severe (Kroos M et al. Hum Mutat. 2012;33(8):1161-5). Patients with this class of variant are CRIM-positive. This variant involves a highly conserved nucleotide and amino acid. PolyPhen-2, SIFT, and MutationTaster all predict this variant to be deleterious. -

Jan 25, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 03, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000152.5:c.1082C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 361 (p.Pro361Leu). This variant has been reported in at least 13 individuals with clinical symptoms consistent with Pompe disease including 6 individuals with documented laboratory values showing deficiency of GAA activity below normal range in leukocytes or <1% activity in fibroblasts or another tissue, many of whom were also reported to be showing improvement on enzyme replacement therapy and/or had specific features reported for infantile onset Pompe disease including cardiomyopathy and motor delay (PMID: 21484825, 25139343, 25526786, 26497565, 27344650, 31439017, 31915562) and another patient with features specific for infantile onset Pompe disease, on enzyme replacement therapy (PMID: 30023291). Pseudodeficiency variants, c.1726G>A and c.2065G>A, were reported to be absent in at least one of these patients (PMID: 25526786) (PP4_Moderate). Of the patients reported with this variant, four are compound heterozygous for the variant and another variant in GAA classified as pathogenic by the ClinGen LSD VCEP including c.784G>A (p.Glu262Lys) (PMID: 31915562; confirmed in trans by parental DNA testing) and c.1933G>A (p.Asp645Asn) (PMID: 26497565, 27344650; phase unknown), c.1935C>A (p.Asp645Glu) (PMID: 31439017; phase unknown), and c.2238G>C (p.Trp746Cys) (PMID: 35123860; phase unknown). In addition, two homozygotes have been reported (PMID: 30023291, 31931849), one of whom was identified by next generation sequencing panel for limb girdle muscle weakness, and not counted due to no report of follow up enzyme studies to confirm diagnosis of Pompe disease (PMID: 31931849) (PM3_Strong). Additional patients have been reported with the variant in compound heterozygosity with another variant including c.503G>C (p.Arg168Pro) (PMID: 25526786), c.953T>C (p.Met318Thr) (PMID: 25139343), c.1309C>T (p.Arg437Cys) (PMID: 12601120, 27692865), c.1432G>A (p.Gly478Arg) (PMID: 25213570), c.1979G>A (p.Arg660His) (PMID: 21484825), and c.1551+1G>C (PMID: 16917947). In these cases, the allelic data will be used in the assessment of the second variant and was not applied to PM3 here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. When expressed in COS cells and GAA deficient fibroblasts, this variant resulted in <4% wild type GAA activity in three different studies (PMID: 12601120, 19862843, 22644586) and showed evidence of abnormal synthesis and processing on Western blot (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.951 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant at the same codon, c.1082C>A (p.Pro361Arg) has been reported (PMID: 31076647). The classification of p.Pro163Leu will be used in the assessment of p.Pro361Arg and, therefore, PM5 is not applied here. There is a ClinVar entry for this variant (Variation ID: 403712, 2 star review status) with four submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022. -

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 361 of the GAA protein (p.Pro361Leu). This variant is present in population databases (rs755253527, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 12601120, 16917947, 25213570, 27344650, 30023291). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 403712). 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: 12601120). For these reasons, this variant has been classified as Pathogenic. -

Jan 22, 2020

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous p.Pro361Leu variant in GAA has been reported in at least 15 individuals (including 6 Chinese, 2 Italian, and 1 from the UK) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 30023291, 27692865, 26497565, 25526786, 25213570, 25139343, 21484825, 16917947, 12601120, 24169249, 26685070, 17915575), and has also been reported pathogenic by Claritas Genomics and Invitae in ClinVar (Variation ID: 403712). This variant has been identified in 0.006% (2/34496) of Latino chromosomes and 0.005% (1/21462) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755253527). 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 a minigene assay and COS cells transfected with the variant provide some evidence that the p.Pro361Leu variant may eliminate proteolytically activated GAA and impact GAA activity (PMID: 22644586, 12601120). 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. This variant was reported in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II (PMID: 21484825, 12601120, 26497565, 16917947, 26685070, 30023291, 27692865, 25213570, 25139343). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue (PMID: 21484825, 26497565, 25139343, 12601120). One additional variant at the same position, p.Pro361Arg, has been reported as a VUS in ClinVar (Variation ID: 289367). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4 (Richards 2015). -

Oct 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Oct 06, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 26, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with significantly reduced enzymatic activity compared to wildtype (Kroos et al., 2012); 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: 28592009, 30281819, 25213570, 12601120, 16917947, 27344650, 30275481, 30023291, 34134972, 31086307, 22644586, 34539730, 31915562) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H

PhyloP100

7.4

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.90

Gain of catalytic residue at P361 (P = 0.0183);Gain of catalytic residue at P361 (P = 0.0183);

MVP

0.97

MPC

0.55

ClinPred

1.0

GERP RS

4.8

Varity_R

0.95

gMVP

0.94

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over