chr17-80108811-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3PM2_SupportingPM3PS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1309C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 437 (p.Arg437Cys). This variant has been reported in at least 16 East Asian individuals with late onset Pompe disease (PMID:34356580) including 11 individuals with documented laboratory values reporting GAA activity <10% normal in muscle or skin fibroblasts or in the affected range in a clinically validated dried blood spot assay and/or histological features consistent with Pompe disease in muscle, and/or on enzyme replacement therapy for Pompe disease (PMID 22521436, 29786057, 27692865, 30360039)(PP4_Moderate). Ten individuals are reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including one confirmed in trans, c.1082C>T (p.Pro361Leu) (PMID:12601120), and 9 phase unknown, c.796C>T (p.Pro266Ser) (PMID:25526786), c.1082C>T (p.Pro361Leu) (PMID:27692865), c.1316T>A (p.Met439Lys) (PMID:25388776), c.1822C>T (p.Arg608Ter) (PMID:30360039), c.1978C>T (p.Arg600Cys) (PMID:29124014, 3 probands), c.2238G>C (p.Trp746Cys) (PMID:27692865), c.2297A>G (p.Tyr766Cys) (PMID:29124014) (PM3_VeryStrong). The variant has also been reported in compound heterozygosity with c.1544T>A (p.Met515Lys) (PMID:24190153), c.1562A>T (p.Glu521Val) (PMID:29786057), c.1857C>G (p.Ser619Arg) (PMID:291240140, c.2051C>A (p.Pro684Gln) (PMID:29451150), c.2177C>G (p.Pro726Arg) (PMID:29124014), and c.2297A>C (p.Tyr766Ser) (PMID:22521436). The allelic data from these patients will be used in the classification of the second variant and is not included here in order to avoid circular logic. Additional patients have also been reported but the data was not included because the cDNA sequences of the variants was not included (PMID:18495398, 21471980, 21704464). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (2/21914 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cells showed no detectable GAA enzyme activity, and another study showed abnormal synthesis and processing of GAA when the variant was expressed in COS cells, indicating that this variant may impact protein function (PMID:12601120, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.782, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A novel variant at the same amino acid position, c.1310G>A (p.Arg437His) has been reported in a patient with Pompe disease (PMID:25681614) but has not yet been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, PM5 is not applied. There is a ClinVar entry for this variant (Variation ID: 189082, 2 star review status) with 6 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 (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274356/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 1.49

Publications

19 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 7 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.1309C>T	p.Arg437Cys	missense_variant	Exon 8 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.1309C>T	p.Arg437Cys	missense_variant	Exon 8 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000460

AC:

AN:

217456

AF XY:

0.00000845

show subpopulations

Gnomad AFR exome

AF:

0.0000757

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000830

AC:

AN:

1445940

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

718182

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33206

American (AMR)

AF:

0.00

AC:

AN:

42548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25798

East Asian (EAS)

AF:

0.0000515

AC:

AN:

38854

South Asian (SAS)

AF:

0.00

AC:

AN:

84282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00000543

AC:

AN:

1104830

Other (OTH)

AF:

0.00

AC:

AN:

59724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:11

Oct 11, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.78 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.87 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189082 /PMID: 12601120 /3billion dataset). A different missense change at the same codon (p.Arg437Ser) has been reported to be associated with GAA related disorder (ClinVar ID: VCV002155070). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

May 05, 2020

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.1309C>T (p.Arg437Cys) 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 4.6e-06 in 217456 control chromosomes. c.1309C>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. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of wild-type enzyme activity (Tajima_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 10, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 22, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg437Cys variant in GAA has been reported in 13 individuals (including 7 Japanese, 3 Chinese, and 2 Korean) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 18495398, 22521436, 12601120, 23884227, 24169249, 25388776, 21984055, 25526786, 17805474, 24190153, 24872213, 21704464), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae in ClinVar (Variation ID: 189082). This variant has been identified in 0.009% (2/21914) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770610356). 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 provide some evidence that the p.Arg437Cys variant may impact GAA activity and levels (PMID: 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. However, the Arginine (Arg) at position 437 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg437Cys variant is pathogenic (PMID: 22521436, 12601120, 17805474). One additional variant at the same position, p.Arg437His, has been reported as a VUS in ClinVar (Variation ID: 456374). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on low GAA activity, consistent with disease (PMID: 12601120, 17805474, 22521436). 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 pathogenic and likely pathogenic variants in individuals with Glycogen Storage Disease II and evidence from in vitro functional studies. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, PP4 (Richards 2015). -

May 21, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 437 of the GAA protein (p.Arg437Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 12601120, 17805474, 29124014). 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: 189082). 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: 12601120). For these reasons, this variant has been classified as Pathogenic. -

Aug 07, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 30, 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.1309C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 437 (p.Arg437Cys). This variant has been reported in at least 16 East Asian individuals with late onset Pompe disease (PMID: 34356580) including 11 individuals with documented laboratory values reporting GAA activity <10% normal in muscle or skin fibroblasts or in the affected range in a clinically validated dried blood spot assay and/or histological features consistent with Pompe disease in muscle, and/or on enzyme replacement therapy for Pompe disease (PMID 22521436, 29786057, 27692865, 30360039)(PP4_Moderate). Ten individuals are reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including one confirmed in trans, c.1082C>T (p.Pro361Leu) (PMID: 12601120), and 9 phase unknown, c.796C>T (p.Pro266Ser) (PMID: 25526786), c.1082C>T (p.Pro361Leu) (PMID: 27692865), c.1316T>A (p.Met439Lys) (PMID: 25388776), c.1822C>T (p.Arg608Ter) (PMID: 30360039), c.1978C>T (p.Arg600Cys) (PMID: 29124014, 3 probands), c.2238G>C (p.Trp746Cys) (PMID: 27692865), c.2297A>G (p.Tyr766Cys) (PMID: 29124014) (PM3_VeryStrong). The variant has also been reported in compound heterozygosity with c.1544T>A (p.Met515Lys) (PMID: 24190153), c.1562A>T (p.Glu521Val) (PMID: 29786057), c.1857C>G (p.Ser619Arg) (PMID: 291240140, c.2051C>A (p.Pro684Gln) (PMID: 29451150), c.2177C>G (p.Pro726Arg) (PMID: 29124014), and c.2297A>C (p.Tyr766Ser) (PMID: 22521436). The allelic data from these patients will be used in the classification of the second variant and is not included here in order to avoid circular logic. Additional patients have also been reported but the data was not included because the cDNA sequences of the variants was not included (PMID: 18495398, 21471980, 21704464). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00009 (2/21914 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cells showed no detectable GAA enzyme activity, and another study showed abnormal synthesis and processing of GAA when the variant was expressed in COS cells, indicating that this variant may impact protein function (PMID: 12601120, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.782, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A novel variant at the same amino acid position, c.1310G>A (p.Arg437His) has been reported in a patient with Pompe disease (PMID: 25681614) but has not yet been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, PM5 is not applied. There is a ClinVar entry for this variant (Variation ID: 189082, 2 star review status) with 6 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 (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. -

Jan 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. -

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Apr 23, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies with this variant showed no detectable GAA activity in Ad5-SV40 immortalized human GAA-deficient fibroblast cells and abnormal processing and synthesis of GAA when expressed in COS cells (Lam et al., 2003; Flanagan et al., 2009); 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: 23884227, 21471980, 12601120, 21704464, 27692865, 24190153, 24169249, 21984055, 29124014, 29451150, 30281819, 25526786, 24872213, 18495398, 21940687, 25388776, 17805474, 22521436, 11053688, 22253258, 19343043, 34405923, 34922579, 19862843) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

.;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.0

H;H

PhyloP100

1.5

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.62

MutPred

0.89

Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);

MVP

1.0

MPC

0.56

ClinPred

0.96

GERP RS

3.5

Varity_R

0.82

gMVP

0.84

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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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