rs142967546

Positions:

chr17-80107705-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.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID:36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID:31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID:33202836), as well as in five individuals reported to have later-onset disease (PMID:22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID:36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID:33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815025/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00054 ( 1 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:12U:5

Conservation

PhyloP100: 2.23

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.841C>T	p.Arg281Trp	missense_variant	4/20	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.841C>T	p.Arg281Trp	missense_variant	4/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.000313

AC:

AN:

150096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000981

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:

0.000623

Gnomad OTH

AF:

0.000490

GnomAD3 exomes

AF:

0.000206

AC:

AN:

247128

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

134154

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000544

AC:

794

AN:

1460482

Hom.:

Cov.:

AF XY:

0.000546

AC XY:

397

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000664

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000306

AC:

AN:

150216

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

AN XY:

73270

show subpopulations

Gnomad4 AFR

AF:

0.0000978

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:

0.000608

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.000312

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:7Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	The GAA c.841C>T; p.Arg281Trp variant (rs142967546) is reported in a carrier of Pompe disease identified by newborn screening (Wittmann 2012) and in an individual with suspected late onset Pompe disease who carried a second GAA variant (Ficicioglu 2020). The p.Arg281Trp variant is classified as likely pathogenic by an expert panel in ClinVar (Variation ID: 283894). It is found in the general population with an overall allele frequency of 0.02% (57/277866 alleles) in the Genome Aggregation Database. The arginine at codon 281 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.786). Based on available information, this variant is considered to be likely pathogenic. References: Ficicioglu C et al. Newborn Screening for Pompe Disease: Pennsylvania Experience. Int J Neonatal Screen. 2020 Nov 13;6(4):89. PMID: 33202836. Wittmann J et al. Newborn screening for lysosomal storage disorders in hungary. JIMD Rep. 2012;6:117-25. PMID: 23430949. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 281 of the GAA protein (p.Arg281Trp). This variant is present in population databases (rs142967546, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Pompe disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 283894). 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%. This variant disrupts the p.Arg281 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2023	The p.Arg281Trp variant in GAA has been reported in at least 4 compound heterozygous individuals with biochemically confirmed Pompe disease and one compound heterozygous individual with sudden death under the age of 45 (Angelini 2011 PMID: 22081099, Kishnani 2019 PMID: 31086307, Salfati 2019 PMID: 31847883, Ficicoglu 2020 PMID: 33202836, ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel personal communication 2023). It has also been identified in 0.062% (42/67436) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as likely pathogenic on December 5, 2019 by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (Variation ID 283894). 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 meets criteria to be classified as likely pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PM3_Strong, PP3, PP4. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 13, 2019	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 08, 2024	The NM_000152.5:c.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID: 36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID: 31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID: 33202836), as well as in five individuals reported to have later-onset disease (PMID: 22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID: 36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID: 33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2024	Variant summary: GAA c.841C>T (p.Arg281Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of 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 0.00021 in 247128 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.841C>T has been reported in the literature in individuals affected with Glycogen Storage Disease (examples: Angelini_2012, Liao_2017, Kishnani_2019, Ficicioglu_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 283894). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:4Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GAA: PM3:Strong, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	PP3, PP4_moderate, PM2, PM3_very_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	Identified in an individual with late-onset Pompe disease with significant residual GAA activity in muscle; a second variant in the GAA gene was not identified in this individual (Angelini et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 283894; ClinVar); This variant is associated with the following publications: (PMID: 33560568, 33202836, 34356580, 19343043, 22081099, 31086307, 23430949, 33717985, 33073009, 33073027) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 17, 2011	- -

GAA-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

The GAA c.841C>T variant is predicted to result in the amino acid substitution p.Arg281Trp. This variant has been reported along with a second causative variant in individuals with late-onset Pompe disease (LOPD) or by newborn screening (Ficicioglu et al. 2020. PubMed ID: 33202836; Wencel et al. 2021. PubMed ID: 36299500). This variant was also reported in an individual with LOPD and an individual identified by newborn screening; a second variant was not identified in either individual (Angelini et al. 2012. PubMed ID: 22081099; Wittmann et al. 2012. PubMed ID: 23430949). It was also identified along with a likely benign intronic variant in an individual diagnosed with Pompe disease (Table S3, Kishnani et al. 2019. PubMed ID: 31086307). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from pathogenic to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/283894). The ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel interprets this variant as likely pathogenic and cites internal data from clinical diagnostic laboratories in their interpretation, mentioning the c.841C>T (p.Arg281Trp) variant was found with a second pathogenic variant (c.2481+102_2646+31del or c.2161del) in two individuals, with the variants confirmed to be on opposite alleles (i.e., in trans) in one of the individuals. Based on the collective evidence, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.2

.;H;H

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.4

.;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.95

MVP

1.0

MPC

0.55

ClinPred

0.98

GERP RS

2.8

Varity_R

0.94

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

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