rs140826989
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000152.5(GAA):c.1548G>A(p.Trp516Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
GAA
NM_000152.5 stop_gained
NM_000152.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.39
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-80110837-G-A is Pathogenic according to our data. Variant chr17-80110837-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189025.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-80110837-G-A is described in Lovd as [Pathogenic]. Variant chr17-80110837-G-A is described in Lovd as [Pathogenic]. Variant chr17-80110837-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.1548G>A | p.Trp516Ter | stop_gained | 10/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.1548G>A | p.Trp516Ter | stop_gained | 10/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135856
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:12
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Trp516Ter variant in GAA has been reported in at least 16 individuals (including at least 10 Caucasian individuals) with Glycogen Storage Disease II (PMID: 22676651, 25155446, 14695532, 17027861, 15048888, 18757064, 20826098, 22237443, 25243733, 24715333, 22252923, 26873529, 23601496), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189025). This variant has been identified in 0.002% (2/128904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140826989). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 516, 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 combination with 3 pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp516Ter variant is pathogenic (PMID: 20826098, 25243733, 22237443, 22676651; Variation ID: 4031, 4033). The phenotype of six individuals compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity within fibroblasts or a dried blood spot (PMID: 20826098, 23601496, 22237443, 25243733, 26873529, 22676651). 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_Strong, PM2, PP4 (Richards 2015). - |
Pathogenic, reviewed by expert panel | curation | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | Feb 14, 2020 | This variant, c.1548G>A (p.Trp516Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP's specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Therefore, PP4 and PM3_Strong can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). There is a ClinVar entry for this variant (Variation ID: 189025, 2 star review status) with 5 submitters classifying the variant as pathogenic and one 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: PVS1, PM2, PM3_Strong, PP4. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.1548G>A;p.(Trp516*) variant creates a premature translational stop signal in the GAA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 189025; PMID: 32317649; 30155607; 29181627; 29122469; 26873529) - PS4. The variant is present at low allele frequencies population databases (rs140826989 – gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp516*) was detected in trans with a pathogenic variant (PMID: 32317649; 29181627; 29122469; 26873529) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 09, 2019 | Variant summary: GAA c.1548G>A (p.Trp516X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes. c.1548G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- eg Hermans_2004, deVries_2010, Messinger_2012, Stepien_2016). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This nonsense variant found in exon 10 of 20 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with Glycogen storage disease II (PMID: 14695532, 29181627, 29122469, 24715333). Loss-of-function variation in GAA is an established mechanism of disease (PMID:18425781, 22252923). This variant has been observed in individuals with low alpha-glucosidase enzyme activity, suggestive of Glycogen storage disease II (PMID: 25243733, 22676651).The c.1548G>A (p.Trp516Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00007 (2/282510) and thus is presumed to be rare. Based on the available evidence, the c.1548G>A (p.Trp516Ter) variant is classified as a Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change creates a premature translational stop signal (p.Trp516*) 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 (rs140826989, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Pompe disease and low alpha-glucosidase enzyme activity (PMID: 14695532, 22676651, 24715333, 25243733, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 189025). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Therapies Laboratory, Murdoch University | Jan 07, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 08, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 20, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 16, 2021 | - - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Sep 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2022 | Reported in multiple unrelated patients with glycogen storage disease type II (GSDII) (Hermans et al. 2004; van et al. 2015; Elder et al. 2013; Bergsma et al. 2015; de Vries JM et al. 2010); Not observed at significant frequency in large population cohorts (gnomAD); 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: 22252923, 18757064, 34134972, 31965297, 32888769, 31086307, 25525159, 25155446, 29181627, 25541616, 22676651, 24715333, 20826098, 23601496, 15048888, 25243733, 14695532) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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 | Eurofins Ntd Llc (ga) | Jun 08, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at