Submissions for variant NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

gnomAD frequency: 0.00063  dbSNP: rs121907943

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000004249	SCV001371731	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	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.
GeneDx	RCV000255539	SCV000321686	pathogenic	not provided	2020-02-21	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000255539	SCV000331031	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004249	SCV000626581	pathogenic	Glycogen storage disease, type II	2025-01-23	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004249	SCV000695654	pathogenic	Glycogen storage disease, type II	2016-09-29	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000004249	SCV000893478	pathogenic	Glycogen storage disease, type II	2024-04-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000004249	SCV001193985	pathogenic	Glycogen storage disease, type II	2019-12-20	criteria provided, single submitter	clinical testing	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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000004249	SCV001251812	pathogenic	Glycogen storage disease, type II	2020-05-03	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000004249	SCV001364292	pathogenic	Glycogen storage disease, type II	2020-04-02	criteria provided, single submitter	research	ACMG codes: PVS1, PM3, PM3, PP5
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000004249	SCV001422773	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	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).
Baylor Genetics	RCV000004249	SCV001524477	pathogenic	Glycogen storage disease, type II	2024-03-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255539	SCV002023863	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000004249	SCV002318732	pathogenic	Glycogen storage disease, type II	2022-03-22	criteria provided, single submitter	clinical testing	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000255539	SCV002502519	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000004249	SCV002506186	pathogenic	Glycogen storage disease, type II	2022-03-09	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000004249	SCV004101335	pathogenic	Glycogen storage disease, type II	2023-06-09	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000004249	SCV004183357	pathogenic	Glycogen storage disease, type II	2024-01-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM3 very strong, PP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004249	SCV004847299	pathogenic	Glycogen storage disease, type II	2023-07-21	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255539	SCV005413280	pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	PP4, PM3_very_strong, PVS1
Ambry Genetics	RCV004991965	SCV005591970	pathogenic	Cardiovascular phenotype	2024-08-06	criteria provided, single submitter	clinical testing	The p.R854* pathogenic mutation (also known as c.2560C>T), located in coding exon 17 of the GAA gene, results from a C to T substitution at nucleotide position 2560. This changes the amino acid from an arginine to a stop codon within coding exon 17. This variant has been identified in the homozygous state and/or in conjunction with other GAA variant(s) in many individual(s) with features consistent with glycogen storage disease type II (also known as Pompe disease), and has been reported as a common variant occurring globally, being particularly frequent in African/African-American populations (Becker JA et al. Am J Hum Genet, 1998 Apr;62:991-4; McCready ME et al. Mol Genet Metab, 2007 Dec;92:325-35; Abbott MA et al. Mol Genet Metab, 2011 Dec;104:583-6; Berrier KL et al. Genet Med, 2015 Nov;17:912-8; Mori M et al. Mol Genet Metab, 2017 Dec;122:189-197; Reuser AJJ et al. Hum Mutat, 2019 Nov;40:2146-2164; Sánchez-Sánchez LM et al. Gac Med Mex, 2022;158:265-270; Martinez-Montoya V et al. Mol Genet Genomic Med, 2024 Jul;12:e2480). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000004249	SCV005865788	pathogenic	Glycogen storage disease, type II	2025-02-10	criteria provided, single submitter	research	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. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
OMIM	RCV000004249	SCV000024415	pathogenic	Glycogen storage disease, type II	1998-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000004249	SCV000086728	not provided	Glycogen storage disease, type II		no assertion provided	literature only
Natera, Inc.	RCV000004249	SCV001463864	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255539	SCV001930660	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255539	SCV001958779	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255539	SCV001972424	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904805	SCV004718552	pathogenic	GAA-related disorder	2024-08-05	no assertion criteria provided	clinical testing	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.