rs121907943

Positions:

chr17-80118271-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PP4PM3

This summary comes from the ClinGen Evidence Repository: This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Very Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340130/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

GAA
NM_000152.5 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:24O:1

Conservation

PhyloP100: -0.165

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 Pathogenic. Variant got 11 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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.2560C>T	p.Arg854Ter	stop_gained	18/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2560C>T	p.Arg854Ter	stop_gained	18/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000478

GnomAD3 exomes

AF:

0.000175

AC:

AN:

246224

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

133162

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000335

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000611

AC:

AN:

1456186

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

723836

show subpopulations

Gnomad4 AFR exome

AF:

0.00201

Gnomad4 AMR exome

AF:

0.000181

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000701

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000585

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:16Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	The GAA c.2560C>T; p.Arg854Ter variant (rs121907943) is reported in the literature as homozygous and as compound heterozygous in numerous individuals affected with glycogen storage disease type II (Becker 1998, McCready 2007, Messinger 2012, Reuser 2019). Additionally, this variant is the most common variant reported in individuals with infantile onset Pompe disease (Reuser 2019), especially in those of African descent. This variant is reported in ClinVar and is classified as pathogenic by an expert panel (Variation ID: 4034). This variant is found in the African population with an allele frequency of .2% (47/24858 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Becker JA et al. The African origin of the common mutation in African American patients with glycogen-storage disease type II. Am J Hum Genet. 1998 Apr;62(4):991-4. PMID: 9529346. McCready ME et al. Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. Mol Genet Metab. 2007 Dec;92(4):325-35. PMID: 17723315. Messinger YH et al. Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med. 2012 Jan;14(1):135-42. PMID: 22237443. Reuser AJJ et al. GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry. Hum Mutat. 2019 Nov;40(11):2146-2164. PMID: 31342611. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002347).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17723315, 23825616, 22252923, 25741864, 31193175, 31193175). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 09, 2023	The GAA c.2560C>T (p.Arg854Ter) nonsense variant has been shown to result in loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This has been demonstrated experimentally by analyzing cDNA obtained from patient cells (PMID: 8094613). This variant is the most common cause of disease in individuals of African descent and is considered to be a founder variant (PMID: 20301438). Across a selection of the available literature, the c.2560C>T variant has been identified in multiple individuals with biochemically confirmed disease in a homozygous and compound heterozygous state with a different pathogenic variant (PMID: 8094613; 9529346; 21889385; 29390460; 29637184). The highest frequency of this allele in the Genome Aggregation Database is 0.00198 in the African population, with no reported homozygous individuals (version 3.1.2). This variant has been classified as pathogenic by at least three submitters, including an expert panel, in ClinVar. This variant has been shown to segregate with disease. Based on the available evidence, the c.2560C>T (p.Arg854Ter) variant is classified as pathogenic for glycogen storage disease, type II. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Arg854*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs121907943, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type II (PMID: 9529346, 17723315, 19588081). ClinVar contains an entry for this variant (Variation ID: 4034). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 05, 2020	This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Very Strong, PP4. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg854Ter variant in GAA has been reported in at least 66 individuals (including 13 African American, 10 Brazilian, 4 Columbian, 4 from the UK, 2 Caucasian, 1 French, 1 Omani, 1 Pakistani, and 1 Dominican/Caucasian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 23430493, 19588081, 26497565, 9529346, 10528311, 16860134, 17723315, 21484825, 18535739, 11071489, 24273659, 23601496, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921, 8094613), and has also been reported pathogenic (by GeneDx, EGL, Counsyl, Invitae, Integrated Genetics, Fulgent Genetics, OMIM, and GeneReviews) in ClinVar (Variation ID: 4034). This variant has been identified in 0.189% (47/24858) of African chromosomes and 0.020% (7/34802) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907943). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 854, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in the homozygous state and in combination with reported pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg854Ter variant is pathogenic (PMID: 23430493, 19588081, 26497565, 9529346, 10528311, 16860134, 17723315, 21484825, 18535739, 11071489, 24273659, 23601496, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921, 8094613). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their CRIM-negative status and reduced GAA activity detected by assays of relevant tissues, consistent with disease (PMID: 26497565, 23601496, 22237443, 21889385, 11071489, 8094613, 16860134, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 30, 2024	ACMG classification criteria: PVS1, PM3 very strong, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 02, 2020	ACMG codes: PVS1, PM3, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2016	Variant summary: The GAA c.2560C>T (p.Arg854X) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 25/116512 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.002243 (23/10254). These frequencies are lower than the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), but suggest that this variant is of African origin. The variant has been identified in homozygous and compound heterozygous state in patients with Pompe disease, suggesting the variant is causative. Additionally, functional studies indicate that the variant has negligible catalytic activity and that the variant results in a transcript that is either not expressed or unstable. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000152.3(GAA):c.2560C>T(R854) is classified as pathogenic in the context of Pompe disease. Sources cited for classification include the following: PMID 11071489, 19862843, 20472203, 22555271, 9529346, 16702877 and 8094613. Classification of NM_000152.3(GAA):c.2560C>T(R854) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2023	The p.Arg854X variant in GAA has been reported in >20 homozygous or compound heterozygous individuals (with additional pathogenic variants) with clinical features of a glycogen storage disease type II (GSD type II), also known as Pompe disease, and segregated with disease in at least 1 affected individual from 1 family (Hermans 1993 PMID: 8094613, Becker 1998 PMID: 9529346, McCready 2007 PMID: 17723315, Oba-Shinjo 2009 PMID: 19588081, Abbott 2011 PMID: 21889385, Elder 2013 PMID: 23601496, Banugaria 2013 PMID: 23825616, Berrier 2015 PMID: 25741864, Broomfield 2016 PMID: 26497565, Desai 2019 PMID: 31193175, Reuser 2019 PMID: 31342611). Some of these individuals have a CRIM-negative status (absent GAA Cross Reactive Immunological Material) and reduced GAA activity by enzyme assays. This variant is the most common variant reported in individuals with infantile onset Pompe disease (Reuser 2019 PMID: 31342611), especially in those of African descent. It has also been identified in 0.198% (82/41414) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for GSD type II. This nonsense variant leads to a premature termination codon at position 854, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive GSD type II. In vitro functional studies provide some evidence that this variant causes loss of expression of alpha-glucosidase (Hermans 1993 PMID: 8094613). Additionally, this variant was classified as Pathogenic on May 5, 2020 by the ClinGen-approved Lysosomal Storage Disorder expert panel (Variation ID 4034). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease type II (GSD type II), or Pompe disease. ACMG/AMP Criteria applied: PVS1, PM3_Very_Strong, PS3_Supporting. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 09, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2020	Common variant associated with glycogen storage disease II (GSD II; Pompe disease) in individuals of African and African American ancestry; Expression studies of the R845X variant in COS cells showed negligible activity compared to wild-type protein (Hermans et al., 1993); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21889385, 20472203, 30564623, 29637184, 31395954, 22975760, 21228398, 20638881, 22658377, 23430493, 22555271, 27344650, 28694071, 20301438, 9529346, 19588081, 17723315, 29390460, 31980526, 31086307, 31589614, 33202836, 33013846, 8094613) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

GAA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The GAA c.2560C>T variant is predicted to result in premature protein termination (p.Arg854*). This variant has been reported as causative for glycogen storage disease (Hermans et al 1993. PubMed ID: 8094613; Abbott et al 2011. PubMed ID: 21889385). This variant is reported in 0.19% of alleles in individuals of African descent in gnomAD. Nonsense variants in GAA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.064

FATHMM_MKL

Benign

0.11

MutationTaster

Benign

1.0

A;A

Vest4

0.87

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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