ClinVar Genomic variation as it relates to human health
NM_002087.4(GRN):c.26C>A (p.Ala9Asp)
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_002087.4(GRN):c.26C>A (p.Ala9Asp)
Variation ID: 16013 Accession: VCV000016013.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44349190 (GRCh38) [ NCBI UCSC ] 17: 42426558 (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 Feb 20, 2014 May 12, 2024 Jun 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002087.4:c.26C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002078.1:p.Ala9Asp missense NC_000017.11:g.44349190C>A NC_000017.10:g.42426558C>A NG_007886.1:g.9068C>A LRG_661:g.9068C>A LRG_661t1:c.26C>A P28799:p.Ala9Asp - Protein change
- A9D
- Other names
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- Canonical SPDI
- NC_000017.11:44349189:C:A
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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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GRN | - | - |
GRCh38 GRCh37 |
646 | 685 |
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 (3) |
criteria provided, single submitter
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- | RCV000017386.32 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2021 | RCV000084421.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 24, 2022 | RCV001851887.6 |
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
(Aug 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961697.15
First in ClinVar: Oct 08, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001475244.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Found in multiple … (more)
Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Found in multiple individuals with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171176.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis 11
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002117726.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRN function (PMID: 17984093, 29036611, 31600775). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRN function (PMID: 17984093, 29036611, 31600775). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16013). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 16983685, 24494724). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 9 of the GRN protein (p.Ala9Asp). (less)
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Pathogenic
(Apr 01, 2011)
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no assertion criteria provided
Method: literature only
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FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037658.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia (607485), originally described as having 'hereditary dysphasic disinhibition dementia' (Lendon et … (more)
In affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia (607485), originally described as having 'hereditary dysphasic disinhibition dementia' (Lendon et al., 1998), Mukherjee et al. (2006) identified a heterozygous C-A transversion in exon 1 of the GRN gene, resulting in an ala9-to-asp (A9D) substitution. (Mukherjee et al. (2006) erroneously stated that the transversion occurred at c.4068; Mukherjee et al. (2008) stated the correct position as c.26.) The A9D substitution is predicted to occur in or near the binding site of the signal recognition particle, which targets proteins to the endoplasmic reticulum membrane. Mukherjee et al. (2008) reported that the A9D mutation resulted in normal levels of GRN mRNA, but about 50% decreased levels of secreted GRN protein in cell cultures from affected patients. Further in vitro studies showed that the A9D mutant protein was not glycosylated and was detected in the Golgi and cytosol, but not throughout the secretory pathway like the wildtype protein. The findings indicated that the mutation resulted in transcription of the protein with a defect in trafficking that likely resulted in functional haploinsufficiency. Shankaran et al. (2008) found that expression of the A9D mutation in HeLa cells resulted in cytoplasmic missorting with extremely low protein expression. Chen-Plotkin et al. (2011) found the A9D mutation (26C-A) in 6 (6.2%) of 97 unrelated probands with FTLD due to GRN mutations. Those with the A9D mutation appeared to have earlier disease onset and more parkinsonian features compared to patients with other GRN mutations. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116557.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_281
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not provided
(-)
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no classification provided
Method: literature only
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GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001245407.2
First in ClinVar: May 04, 2020 Last updated: Oct 01, 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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Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. | Valdez C | Human molecular genetics | 2020 | PMID: 31600775 |
The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency. | Saracino D | Neurobiology of aging | 2020 | PMID: 31262553 |
Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability. | Pinarbasi ES | Cell reports | 2018 | PMID: 29874572 |
Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients. | Valdez C | Human molecular genetics | 2017 | PMID: 29036611 |
Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused by progranulin gene mutation. | Armstrong RA | The International journal of neuroscience | 2014 | PMID: 24494724 |
Clinicopathologic variability of the GRN A9D mutation, including amyotrophic lateral sclerosis. | Cannon A | Neurology | 2013 | PMID: 23596077 |
Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. | Chen-Plotkin AS | Archives of neurology | 2011 | PMID: 21482928 |
In vivo and postmortem clinicoanatomical correlations in frontotemporal dementia and parkinsonism linked to chromosome 17. | Ghetti B | Neuro-degenerative diseases | 2008 | PMID: 18322394 |
Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. | Mukherjee O | Human mutation | 2008 | PMID: 18183624 |
Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. | Shankaran SS | The Journal of biological chemistry | 2008 | PMID: 17984093 |
Corticobasal syndrome associated with the A9D Progranulin mutation. | Spina S | Journal of neuropathology and experimental neurology | 2007 | PMID: 17917583 |
HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. | Mukherjee O | Annals of neurology | 2006 | PMID: 16983685 |
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. | Gass J | Human molecular genetics | 2006 | PMID: 16950801 |
Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. | Lendon CL | Neurology | 1998 | PMID: 9633693 |
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Text-mined citations for rs63751243 ...
HelpRecord last updated May 12, 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.