ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.2185del (p.Leu729fs)
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.2185del (p.Leu729fs)
Variation ID: 370552 Accession: VCV000370552.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80113361 (GRCh38) [ NCBI UCSC ] 17: 78087160 (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 Nov 19, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.2185del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Leu729fs frameshift NM_000152.4:c.2185delC NM_001079803.3:c.2185del NP_001073271.1:p.Leu729fs frameshift NM_001079804.3:c.2185del NP_001073272.1:p.Leu729fs frameshift NC_000017.11:g.80113362del NC_000017.10:g.78087161del NG_009822.1:g.16807del LRG_673:g.16807del LRG_673t1:c.2185del - Protein change
- L729fs
- Other names
- NM_000152.5(GAA):c.2185del
- p.Leu729fs
- Canonical SPDI
- NC_000017.11:80113360:CC:C
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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 |
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 (6) |
reviewed by expert panel
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Nov 19, 2021 | RCV000412465.15 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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 19, 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: SCV002032108.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
The NM_000152.5:c.2185del (p.Leu729TrpfsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in … (more)
The NM_000152.5:c.2185del (p.Leu729TrpfsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in three individuals with infantile onset Pompe disease (PMIDs 19588081, 24269976, 28394184)(PP4). One of these individuals is homozygous for the variant (PMID 19588081)(PM3_Supporting); another individual is heterozygous for the variant but a second variant was not found (PMID, 24269976), and one is compound heterozygous for the variant and c.1935C>A (p.Asp645Glu)(PMID 28394184). The allelic data for this latter patient was used in the assessment of p.Asp645Glu and is not included here to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variant ID 370552; 2 star review status) with one submitter 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 met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting, PM3_Supporting. (less)
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Pathogenic
(Aug 22, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572217.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: GAA c.2185delC (p.Leu729TrpfsX35) 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.2185delC (p.Leu729TrpfsX35) 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 was absent in 199474 control chromosomes (gnomAD). c.2185delC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Oba-Shinjo_2009, Fu_2013, Nio_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. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1), including ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Feb 26, 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: SCV000485900.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 16, 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:
germline
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Invitae
Accession: SCV000937166.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu729Trpfs*35) in the GAA gene. … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu729Trpfs*35) 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 premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 19588081, 28394184). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370552). (less)
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Pathogenic
(Feb 27, 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: SCV004197866.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 16, 2021)
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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: SCV002092111.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Extension of the Pompe mutation database by linking disease-associated variants to clinical severity. | Niño MY | Human mutation | 2019 | PMID: 31254424 |
Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations. | Chen X | Genetic testing and molecular biomarkers | 2017 | PMID: 28394184 |
Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations. | Fu L | Gene | 2014 | PMID: 24269976 |
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 |
Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. | Oba-Shinjo SM | Journal of neurology | 2009 | PMID: 19588081 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/72e2bfe7-2a3a-46d6-8ba6-e8f23acc10d4 | - | - | - | - |
Text-mined citations for rs1057516581 ...
HelpRecord last updated Feb 14, 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.