ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.258dup (p.Asn87fs)
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.258dup (p.Asn87fs)
Variation ID: 282842 Accession: VCV000282842.23
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80104837-80104838 (GRCh38) [ NCBI UCSC ] 17: 78078636-78078637 (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 6, 2016 Feb 14, 2024 Sep 28, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.258dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Asn87fs frameshift NM_000152.5:c.258dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.3:c.258dup NM_001079803.3:c.258dup NP_001073271.1:p.Asn87fs frameshift NM_001079804.3:c.258dup NP_001073272.1:p.Asn87fs frameshift NC_000017.11:g.80104844dup NC_000017.10:g.78078643dup NG_009822.1:g.8289dup LRG_673:g.8289dup - Protein change
- N87fs
- Other names
- NM_000152.5(GAA):c.258dup
- p.Asn87fs
- Canonical SPDI
- NC_000017.11:80104837:CCCCCCC:CCCCCCCC
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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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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 |
2765 | 2815 |
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 (7) |
reviewed by expert panel
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Sep 28, 2021 | RCV000291526.18 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 16, 2022 | RCV000790707.11 |
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
(Sep 28, 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: SCV002032142.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay … (more)
The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 10 patients with this variant and reported to have Pompe disease have been reported. This includes two patients with documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of them on enzyme replacement therapy (PMID 21484825, 31467850), a further 7, at least, patients on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831), and additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623). At least 7 patients are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA (PM3). Another two patients are compound heterozygous for the variant and either c.1195-8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282842, 2 star review status) with five submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific GAA criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. (less)
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Pathogenic
(Aug 18, 2015)
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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: SCV000334520.3
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Feb 09, 2020)
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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: SCV001338289.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: GAA c.258dupC (p.Asn87GlnfsX9) 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.258dupC (p.Asn87GlnfsX9) 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 1.2e-05 in 246016 control chromosomes. c.258dupC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Beesley_1998, Montalvo_2006, Bali_2011, Nallamilli_2018, Kishnani_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422880.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The heterozygous p.Asn87GlnfsTer9 variant in GAA has been reported in 5 individuals (including 1 from the UK and 1 Italian individual) with Glycogen Storage Disease … (more)
The heterozygous p.Asn87GlnfsTer9 variant in GAA has been reported in 5 individuals (including 1 from the UK and 1 Italian individual) with Glycogen Storage Disease II (PMID: 16917947, 26873529, 21484825, 10206684), and has also been reported pathogenic by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 282842). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 87 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is a moderately established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Asn87GlnfsTer9 variant is pathogenic (PMID: 26873529). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with less than 5% of normal GAA activity detected in their fibroblasts (PMID: 21484825, 26873529). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on the predicted impact of the variant and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disorder II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP4 (Richards 2015). (less)
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Pathogenic
(Nov 12, 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:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807224.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 16, 2022)
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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: SCV002021198.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 12, 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: SCV000816240.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn87Glnfs*9) 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.Asn87Glnfs*9) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with glycogen storage disease II (PMID: 10206684, 16917947, 21484825). ClinVar contains an entry for this variant (Variation ID: 282842). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 17, 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: SCV004195446.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453579.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807617.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966803.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. | Kishnani PS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31086307 |
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
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 |
Molecular analysis and protein processing in late-onset Pompe disease patients with low levels of acid α-glucosidase activity. | Bali DS | Muscle & nerve | 2011 | PMID: 21484825 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. | Montalvo AL | Human mutation | 2006 | PMID: 16917947 |
The identification of five novel mutations in the lysosomal acid a-(1-4) glucosidase gene from patients with glycogen storage disease type II. Mutations in brief no. 134. Online. | Beesley CE | Human mutation | 1998 | PMID: 10206684 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/081e8068-c40d-4647-8006-fbecab5b6d86 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b2b5574c-2f8a-4ce7-b32e-aa21d871230d | - | - | - | - |
Text-mined citations for rs761317813 ...
HelpRecord last updated Mar 30, 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.