ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.546G>T (p.Thr182=)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.546G>T (p.Thr182=)
Variation ID: 370637 Accession: VCV000370637.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80105132 (GRCh38) [ NCBI UCSC ] 17: 78078931 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 6, 2017 Feb 14, 2024 Dec 2, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.546G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Thr182= synonymous NM_001079803.3:c.546G>T NP_001073271.1:p.Thr182= synonymous NM_001079804.3:c.546G>T NP_001073272.1:p.Thr182= synonymous NC_000017.11:g.80105132G>T NC_000017.10:g.78078931G>T NG_009822.1:g.8577G>T LRG_673:g.8577G>T LRG_673t1:c.546G>T - Protein change
- Other names
- NM_000152.5(GAA):c.546G>T
- p.Thr182=
- Canonical SPDI
- NC_000017.11:80105131:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2757 | 2807 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
reviewed by expert panel
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Dec 2, 2021 | RCV000410156.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2021 | RCV001782869.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 02, 2021)
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reviewed by expert panel
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Accession: SCV002032139.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact … (more)
The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact splicing of intron 2 (PMID 19609281, 21757382, 33168984). At least 20 patients with Pompe disease and this variant have been reported including 17 patients with documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193); pseudodeficiency variants are confirmed absent in one of these patients (PMID 28433475)(PP4_Moderate). The patients typically have late onset Pompe disease and are of East Asian descent. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1), and c.1935C>A (p.Asp645Glu)(PMID 21757382), and seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3). Consistent with this finding, the computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). Of note, additional variants at this position, c.546G>A (ClinVar Variation ID: 280955) and c.546G>C (ClinVar Variation ID: 281056), have also been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 370637, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PS3, PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. (less)
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Likely pathogenic
(Mar 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000486004.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004197822.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023807.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002217198.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 19609281, 31301153). Experimental studies have shown that this variant affects GAA function (PMID: 21982629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 370637). This variant has been observed in individual(s) with adult onset Pompe disease (PMID: 19609281, 22196155, 30093193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 182 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Assessment of the functional impact on the pre-mRNA splicing process of 28 nucleotide variants associated with Pompe disease in GAA exon 2 and their recovery using antisense technology. | Goina E | Human mutation | 2019 | PMID: 31301153 |
A Case of Adult-onset Pompe Disease with Cerebral Stroke and Left Ventricular Hypertrophy. | Hossain MA | Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association | 2018 | PMID: 30093193 |
Acid phosphatase-positive globular inclusions is a good diagnostic marker for two patients with adult-onset Pompe disease lacking disease specific pathology. | Tsuburaya RS | Neuromuscular disorders : NMD | 2012 | PMID: 22196155 |
Effects of enzyme replacement therapy on five patients with advanced late-onset glycogen storage disease type II: a 2-year follow-up study. | Furusawa Y | Journal of inherited metabolic disease | 2012 | PMID: 21984055 |
Proteasome inhibitors improve the function of mutant lysosomal α-glucosidase in fibroblasts from Pompe disease patient carrying c.546G>T mutation. | Shimada Y | Biochemical and biophysical research communications | 2011 | PMID: 22027144 |
Endoplasmic reticulum stress induces autophagy through activation of p38 MAPK in fibroblasts from Pompe disease patients carrying c.546G>T mutation. | Shimada Y | Molecular genetics and metabolism | 2011 | PMID: 21982629 |
Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: from our experience of 4 cases including an autopsy case. | Kobayashi H | Molecular genetics and metabolism | 2010 | PMID: 20202878 |
Silent exonic mutation in the acid-alpha-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing. | Maimaiti M | Journal of human genetics | 2009 | PMID: 19609281 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Hermans MM | Human mutation | 2004 | PMID: 14695532 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9490a55c-4cd0-44b3-859b-a915cd935f7e | - | - | - | - |
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Text-mined citations for rs143523371 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.