rs121907943
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4PM3PVS1
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
Consequence
NM_000152.5 stop_gained
Scores
Clinical Significance
Conservation
Publications
- glycogen storage disease IIInheritance: 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 onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- glycogen storage disease due to acid maltase deficiency, late-onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GAA | NM_000152.5 | c.2560C>T | p.Arg854* | stop_gained | Exon 18 of 20 | ENST00000302262.8 | NP_000143.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GAA | ENST00000302262.8 | c.2560C>T | p.Arg854* | stop_gained | Exon 18 of 20 | 1 | NM_000152.5 | ENSP00000305692.3 |
Frequencies
GnomAD3 genomes 0.000585 AC: 89AN: 152116Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000175 AC: 43AN: 246224 AF XY: 0.000128 show subpopulations
GnomAD4 exome AF: 0.0000611 AC: 89AN: 1456186Hom.: 0 Cov.: 35 AF XY: 0.0000456 AC XY: 33AN XY: 723836 show subpopulations
Age Distribution
GnomAD4 genome 0.000585 AC: 89AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74428 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:18Other:1
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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/. -
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ACMG codes: PVS1, PM3, PM3, PP5 -
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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. -
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. -
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. -
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. -
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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. -
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. -
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. -
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). -
ACMG classification criteria: PVS1, PM3 very strong, PP4 -
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The p.Arg854* variant in the GAA gene has been previously reported in the compound heterozygous or homozygous state in greater than 20 individuals with Pompe disease (Hermans et al., 1993; McCready et al., 2007; Banugaria et al., 2013; Berrier et al., 2015; Kishnani et al., 2019). This variant has been identified in 47/24,858 African/African American chromosomes (58/277,566 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Accession: VCV000004034.60). The p.Arg854* variant leads to a premature stop codon in exon 18 of 20 coding exons, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Loss-of-function is an established mechanism of disease for the GAA gene (Kroos et al., 2012). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg854* variant as pathogenic for autosomal recessive Pompe disease based on the information above. [ACMG evidence codes used: PVS1; PM3_VeryStrong] -
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 Pathogenic:8
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) -
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PP4, PM3_very_strong, PVS1 -
GAA-related disorder Pathogenic:1
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. -
Cardiovascular phenotype Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at