ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.482_483del (p.Pro161fs)
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.482_483del (p.Pro161fs)
Variation ID: 596146 Accession: VCV000596146.17
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 17q25.3 17: 80105066-80105067 (GRCh38) [ NCBI UCSC ] 17: 78078865-78078866 (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 Dec 16, 2018 Feb 14, 2024 Nov 2, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5(GAA):c.482_483del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.5:c.482_483del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Pro161fs frameshift NM_001079803.3:c.482_483del NP_001073271.1:p.Pro161fs frameshift NM_001079804.3:c.482_483del NP_001073272.1:p.Pro161fs frameshift NC_000017.11:g.80105068_80105069del NC_000017.10:g.78078867_78078868del NG_009822.1:g.8513_8514del LRG_673:g.8513_8514del LRG_673t1:c.482_483del - Protein change
- P161fs
- Other names
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- Canonical SPDI
- NC_000017.11:80105065:CCCC:CC
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 13, 2020 | RCV000731885.9 | |
Pathogenic (4) |
reviewed by expert panel
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Nov 2, 2020 | RCV001219022.9 |
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
(Nov 02, 2020)
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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: SCV001443288.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant, c.482_483del (p.Pro161GlnfsTer15), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene … (more)
This variant, c.482_483del (p.Pro161GlnfsTer15), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001836 in the European non-Finnish population, meeting PM2. Five individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, three are compound heterozygous for c.-32-13T>G (PMID 9196050, 26873529), one is compound heterozygous for c.-32-3C>A (PMID 21550241; a patient with a similar description is reported in PMIDs 30155607, 21803581), and the second variant was unidentified in the remaining patient (PMID 9196050). The phase of the variants is unknown in these cases. The in trans data for the patient who is compound heterozygous for c.-32-3C>A will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, PM3_Supporting is met. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). There is a ClinVar entry for this variant (Variation ID: 596146, 1 star review status) with one submitter classifying the variant as 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_Supporting, PP4. (less)
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Pathogenic
(Feb 14, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000859753.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 01, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002051003.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: GAA c.482_483delCC (p.Pro161GlnfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GAA c.482_483delCC (p.Pro161GlnfsX15) 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 8.2e-06 in 245102 control chromosomes (gnomAD). c.482_483delCC has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Nicolino_1997, Stepien_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 03, 2022)
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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: SCV004197881.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 13, 2020)
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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: SCV002021182.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 15, 2024)
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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: SCV001390942.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro161Glnfs*15) in the GAA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Pro161Glnfs*15) 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 (rs764750389, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 9196050, 26873529, 28648663). ClinVar contains an entry for this variant (Variation ID: 596146). For these reasons, this variant has been classified as Pathogenic. (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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Late-onset Pompe disease (LOPD) in Belgium: clinical characteristics and outcome measures. | Vanherpe P | Orphanet journal of rare diseases | 2020 | PMID: 32248831 |
Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study. | Semplicini C | Journal of inherited metabolic disease | 2018 | PMID: 30155607 |
Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease. | Papadopoulos C | Molecular genetics and metabolism | 2017 | PMID: 28648663 |
Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years. | Stepien KM | Molecular genetics and metabolism | 2016 | PMID: 26873529 |
Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. | Bali DS | American journal of medical genetics. Part C, Seminars in medical genetics | 2012 | PMID: 22252923 |
Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: Involvement patterns. | Carlier RY | Neuromuscular disorders : NMD | 2011 | PMID: 21803581 |
Recombinant human acid alpha-glucosidase (rhGAA) in adult patients with severe respiratory failure due to Pompe disease. | Orlikowski D | Neuromuscular disorders : NMD | 2011 | PMID: 21550241 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. | Laforêt P | Neurology | 2000 | PMID: 11071489 |
Glycogen-storage disease type II (acid maltase deficiency): identification of a novel small deletion (delCC482+483) in French patients. | Nicolino M | Biochemical and biophysical research communications | 1997 | PMID: 9196050 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/38310e9d-9be4-498f-9717-df269b61d625 | - | - | - | - |
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Text-mined citations for rs764750389 ...
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.