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NM_002087.4(GRN):c.1297C>T (p.Arg433Trp)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(4);Likely benign(2);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Sep 27, 2021)
Last evaluated:
Nov 25, 2020
Accession:
VCV000098180.15
Variation ID:
98180
Description:
single nucleotide variant
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NM_002087.4(GRN):c.1297C>T (p.Arg433Trp)

Allele ID
104072
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 44352132 (GRCh38) GRCh38 UCSC
17: 42429500 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_661:g.12010C>T
LRG_661t1:c.1297C>T
NC_000017.10:g.42429500C>T
... more HGVS
Protein change
R433W
Other names
-
Canonical SPDI
NC_000017.11:44352131:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00160 (T)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00175
Exome Aggregation Consortium (ExAC) 0.00433
The Genome Aggregation Database (gnomAD), exomes 0.00548
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00223
The Genome Aggregation Database (gnomAD) 0.00523
The Genome Aggregation Database (gnomAD) 0.00708
1000 Genomes Project 0.00160
Trans-Omics for Precision Medicine (TOPMed) 0.00198
Links
ClinGen: CA225336
dbSNP: rs63750412
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Benign/Likely benign 2 criteria provided, multiple submitters, no conflicts Jun 28, 2017 RCV000576498.2
Benign 1 criteria provided, single submitter Jul 13, 2018 RCV000716742.1
Benign 1 criteria provided, single submitter Nov 25, 2020 RCV001079475.2
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Jan 7, 2019 RCV000084483.7
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
GRN - - GRCh38
GRCh37
290 301

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely Benign
(Oct 07, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000280695.1
Submitted: (May 19, 2016)
Evidence details
Comment:
Converted during submission to Likely benign.
Benign
(Jun 28, 2017)
criteria provided, single submitter
Method: clinical testing
Grn-related frontotemporal lobar degeneration with Tdp43 inclusions
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV000677376.1
Submitted: (Jul 17, 2017)
Evidence details
Publications
PubMed (8)
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Grn-related frontotemporal lobar degeneration with Tdp43 inclusions
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000403349.3
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (10)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Benign
(Jul 13, 2018)
criteria provided, single submitter
Method: clinical testing
Seizures
Allele origin: germline
Ambry Genetics
Accession: SCV000847585.2
Submitted: (Nov 30, 2020)
Evidence details
Comment:
Other strong data;Other strong data supporting benign classification
Benign
(Nov 25, 2020)
criteria provided, single submitter
Method: clinical testing
Ceroid lipofuscinosis, neuronal, 11
Grn-related frontotemporal lobar degeneration with Tdp43 inclusions
Allele origin: germline
Invitae
Accession: SCV000772103.4
Submitted: (Jan 07, 2021)
Evidence details
Benign
(Jan 07, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001940151.1
Submitted: (Sep 27, 2021)
Evidence details
Uncertain significance
(Jun 01, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001151347.7
Submitted: (Jul 04, 2021)
Evidence details
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: not provided
VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116619.1
Submitted: (Feb 13, 2013)
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_308
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers. Benitez BA PLoS genetics 2013 PMID: 23990795
Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Finch N Brain : a journal of neurology 2009 PMID: 19158106
Progranulin variability has no major role in Parkinson disease genetic etiology. Nuytemans K Neurology 2008 PMID: 18838661
Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Brouwers N Neurology 2008 PMID: 18565828
Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Gijselinck I Human mutation 2008 PMID: 18543312
A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Beck J Brain : a journal of neurology 2008 PMID: 18234697
Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. Schymick JC Journal of neurology, neurosurgery, and psychiatry 2007 PMID: 17371905
Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. van der Zee J Human mutation 2007 PMID: 17345602
Clinicopathologic features of frontotemporal dementia with progranulin sequence variation. Spina S Neurology 2007 PMID: 17202431
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Gass J Human molecular genetics 2006 PMID: 16950801

Text-mined citations for rs63750412...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 04, 2021