ClinVar Genomic variation as it relates to human health
NM_002087.4(GRN):c.1252C>T (p.Arg418Ter)
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.1252C>T (p.Arg418Ter)
Variation ID: 98177 Accession: VCV000098177.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44352087 (GRCh38) [ NCBI UCSC ] 17: 42429455 (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 Oct 8, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002087.4:c.1252C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002078.1:p.Arg418Ter nonsense NC_000017.11:g.44352087C>T NC_000017.10:g.42429455C>T NG_007886.1:g.11965C>T LRG_661:g.11965C>T LRG_661t1:c.1252C>T - Protein change
- R418*
- Other names
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- Canonical SPDI
- NC_000017.11:44352086:C: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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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
Help
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 |
655 | 694 |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000084480.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2022 | RCV000995559.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 6, 2023 | RCV001390599.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2022 | RCV002463638.2 |
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 07, 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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Athena Diagnostics
Accession: SCV000613572.2
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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Pathogenic
(Jun 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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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 Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149796.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Nov 06, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001592386.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg418*) in the GRN gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg418*) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia (PMID: 16862116). ClinVar contains an entry for this variant (Variation ID: 98177). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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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 Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002757807.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Clinical Features:
Urinary incontinence (present) , Atypical behavior (present) , Hyperorality (present) , Dementia (present) , Short attention span (present) , Apathy (present) , Parkinsonian disorder (present) … (more)
Urinary incontinence (present) , Atypical behavior (present) , Hyperorality (present) , Dementia (present) , Short attention span (present) , Apathy (present) , Parkinsonian disorder (present) , Apraxia (present) , Memory impairment (present) , Bowel incontinence (present) , Brain atrophy (present) , Delirium (present) , Movement disorder (present) , Cognitive impairment (present) (less)
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Pathogenic
(Oct 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Amyotrophic lateral sclerosis type 10
Affected status: yes
Allele origin:
germline
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Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758562.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PVS1, PM2
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Pathogenic
(Dec 15, 2023)
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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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GeneDx
Accession: SCV005202129.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay (NMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay (NMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34697415, 25525159, 21813674, 23475817, 24993774, 19125255, 19649643, 22608501, 16950801, 32178712, 31707213, 28473694, 28453791, 23742080, 24163244, 23117491, 21482928, 21047645, 31914217, 17698705, 16862116, 22895706, 19204154, 35790423) (less)
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Pathogenic
(Nov 01, 2020)
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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: SCV001250433.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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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: SCV001809013.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely 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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958902.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000116616.1
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_276
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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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Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. | Smith KR | American journal of human genetics | 2012 | PMID: 22608501 |
Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. | Van Deerlin VM | Archives of neurology | 2007 | PMID: 17698705 |
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. | Gass J | Human molecular genetics | 2006 | PMID: 16950801 |
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. | Baker M | Nature | 2006 | PMID: 16862116 |
Text-mined citations for rs63751180 ...
HelpRecord last updated Oct 08, 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.