ClinVar Genomic variation as it relates to human health
NM_004960.4(FUS):c.1574C>T (p.Pro525Leu)
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_004960.4(FUS):c.1574C>T (p.Pro525Leu)
Variation ID: 280110 Accession: VCV000280110.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p11.2 16: 31191431 (GRCh38) [ NCBI UCSC ] 16: 31202752 (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 Oct 20, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004960.4:c.1574C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004951.1:p.Pro525Leu missense NM_001170634.1:c.1571C>T NP_001164105.1:p.Pro524Leu missense NM_001170937.1:c.1562C>T NP_001164408.1:p.Pro521Leu missense NR_028388.2:n.1644C>T non-coding transcript variant NC_000016.10:g.31191431C>T NC_000016.9:g.31202752C>T NG_012889.2:g.16300C>T LRG_655:g.16300C>T LRG_655t1:c.1574C>T LRG_655p1:p.Pro525Leu P35637:p.Pro525Leu - Protein change
- P525L, P521L, P524L
- Other names
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- Canonical SPDI
- NC_000016.10:31191430: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
Help
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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FUS | - | - |
GRCh38 GRCh37 |
533 | 552 |
Conditions - Germline
Condition
Help
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, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000381069.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2020 | RCV001095439.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2022 | RCV001069729.7 | |
FUS-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Sep 26, 2024 | RCV003401225.5 |
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
(May 28, 2014)
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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: SCV000613353.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Mar 26, 2019)
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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: SCV000329963.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Published in vitro functional studies demonstrate mislocalization of the FUS protein product in the cytoplasm instead of the nucleus (Dormann et al., 2010; Coady et … (more)
Published in vitro functional studies demonstrate mislocalization of the FUS protein product in the cytoplasm instead of the nucleus (Dormann et al., 2010; Coady et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24899262, 19450904, 20668261, 21280085, 25173930, 21604077, 20606625, 21949354, 24280224, 25625564, 22778397, 20579074, 22980027, 21907581, 26251528, 25792726, 20668259, 27123482, 25912081, 26298469, 23881933, 21881207, 23056579, 30808650, 19251627, 30684766, 30455313, 31682085, 31630970, 32579787, 32307925, 33580145, 32479602) (less)
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Pathogenic
(Dec 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tremor, hereditary essential, 4
Amyotrophic lateral sclerosis type 6
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: SCV001234919.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 280110). This missense change has been observed in individual(s) with juvenile ALS and amyotrophic lateral sclerosis (ALS) (PMID: 19251627, 20579074, 21604077, 21907581, 22980027, 27123482). In at least one individual the variant was observed to be de novo. 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 sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 525 of the FUS protein (p.Pro525Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FUS function (PMID: 20606625, 21280085, 24899262, 25173930, 25625564, 26251528). (less)
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Pathogenic
(Jan 01, 2024)
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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: SCV001248457.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
FUS: PM1, PM2, PM5, PM6, PS3:Moderate, PS4:Moderate
Number of individuals with the variant: 5
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Pathogenic
(Mar 31, 2020)
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criteria provided, single submitter
Method: research
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Juvenile amyotrophic lateral sclerosis
Affected status: yes
Allele origin:
germline
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Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251072.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 3
Geographic origin: Anatolian Peninsula
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Pathogenic
(Sep 26, 2024)
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no assertion criteria provided
Method: clinical testing
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FUS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118901.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The FUS c.1574C>T variant is predicted to result in the amino acid substitution p.Pro525Leu. This variant has been reported in multiple unrelated individuals with amyotrophic … (more)
The FUS c.1574C>T variant is predicted to result in the amino acid substitution p.Pro525Leu. This variant has been reported in multiple unrelated individuals with amyotrophic lateral sclerosis (ALS, Kwiatkowski et al. 2009. PubMed ID: 19251627; Mackenzie et al. 2011. PubMed ID: 21604077; Leblond et al. 2016. PubMed ID: 27123482; Chen et al. 2021. PubMed ID: 34544842). This variant is located within the conserved C-terminal region of FUS, where missense change is not expected to be tolerated and is considered a hot spot for ALS-causing variants (Lattante et al. 2013. PubMed ID: 23559573). This variant has been interpreted as pathogenic by multiple submitters in ClinVar. Taken together, we interpret this variant as pathogenic. (less)
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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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De novo FUS P525L mutation in Juvenile amyotrophic lateral sclerosis with dysphonia and diplopia. | Leblond CS | Neurology. Genetics | 2016 | PMID: 27123482 |
ALS mutations in TLS/FUS disrupt target gene expression. | Coady TH | Genes & development | 2015 | PMID: 26251528 |
ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. | Sun S | Nature communications | 2015 | PMID: 25625564 |
Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation. | Takanashi K | Biochemical and biophysical research communications | 2014 | PMID: 25173930 |
Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene. | Kent L | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2014 | PMID: 24899262 |
Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing. | Kenna KP | Journal of medical genetics | 2013 | PMID: 23881933 |
The FUS about arginine methylation in ALS and FTLD. | Kaneb HM | The EMBO journal | 2012 | PMID: 23085990 |
FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS. | Niu C | PloS one | 2012 | PMID: 23056579 |
Familial ALS with FUS P525L mutation: two Japanese sisters with multiple systems involvement. | Mochizuki Y | Journal of the neurological sciences | 2012 | PMID: 22980027 |
ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism. | Murakami T | Human molecular genetics | 2012 | PMID: 21949354 |
P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. | Conte A | Neuromuscular disorders : NMD | 2012 | PMID: 21907581 |
The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. | Wang JW | The Journal of clinical investigation | 2011 | PMID: 21881207 |
Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. | Mackenzie IR | Acta neuropathologica | 2011 | PMID: 21604077 |
Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. | Ito D | Annals of neurology | 2011 | PMID: 21280085 |
Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. | Bäumer D | Neurology | 2010 | PMID: 20668261 |
ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. | Dormann D | The EMBO journal | 2010 | PMID: 20606625 |
Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. | Huang EJ | Brain pathology (Zurich, Switzerland) | 2010 | PMID: 20579074 |
Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. | Chiò A | Neurobiology of aging | 2009 | PMID: 19450904 |
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. | Kwiatkowski TJ Jr | Science (New York, N.Y.) | 2009 | PMID: 19251627 |
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Text-mined citations for rs886041390 ...
HelpRecord last updated Oct 20, 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.