ClinVar Genomic variation as it relates to human health
NM_004960.4(FUS):c.1561C>G (p.Arg521Gly)
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.1561C>G (p.Arg521Gly)
Variation ID: 16222 Accession: VCV000016222.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p11.2 16: 31191418 (GRCh38) [ NCBI UCSC ] 16: 31202739 (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 Aug 4, 2017 May 12, 2024 Sep 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004960.4:c.1561C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004951.1:p.Arg521Gly missense NM_001170634.1:c.1558C>G NP_001164105.1:p.Arg520Gly missense NM_001170937.1:c.1549C>G NP_001164408.1:p.Arg517Gly missense NR_028388.2:n.1631C>G non-coding transcript variant NC_000016.10:g.31191418C>G NC_000016.9:g.31202739C>G NG_012889.2:g.16287C>G LRG_655:g.16287C>G LRG_655t1:c.1561C>G LRG_655p1:p.Arg521Gly P35637:p.Arg521Gly - Protein change
- R521G, R520G, R517G
- Other names
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- Canonical SPDI
- NC_000016.10:31191417:C:G
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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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FUS | - | - |
GRCh38 GRCh37 |
524 | 542 |
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 (1) |
no assertion criteria provided
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Feb 27, 2009 | RCV000017609.29 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2022 | RCV000703284.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV002472932.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 16, 2023 | RCV003421921.4 |
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
(Sep 16, 2023)
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criteria provided, single submitter
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: SCV004116658.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FUS c.1561C>G variant is predicted to result in the amino acid substitution p.Arg521Gly. This variant was found in several patients with amyotrophic lateral sclerosis … (more)
The FUS c.1561C>G variant is predicted to result in the amino acid substitution p.Arg521Gly. This variant was found in several patients with amyotrophic lateral sclerosis (ALS) (Kwiatkowski et al. 2009. PubMed ID: 19251627; Millecamps et al. 2010. PubMed ID: 20577002; Yan et al. 2010. PubMed ID: 20668259; Ungaro et al. 2020. PubMed ID: 32951934). Different missense variants in the same codon (p.Arg521Ser, p.Arg521Cys, p.Arg521His, p.Arg521Leu) have been reported in individuals with ALS (e.g., Millecamps et al. 2010. PubMed ID: 20577002), suggesting that substitution of amino acid residue p.Arg521 is not tolerated. A mouse model of the p.Arg521Gly resulted in severe motor deficits phenocopying human disease (Sephton et al. 2014. PubMed ID: 25324524). The c.1561C>G variant is also interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/16222/). It has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033483.6
First in ClinVar: Sep 16, 2023 Last updated: May 12, 2024 |
Comment:
FUS: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jan 07, 2022)
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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: SCV002770807.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations. http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated … (more)
This variant has not been reported in large, multi-ethnic general populations. http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to interfere with cellular localization of the protein (PMID: 20606625, 20674093, 21965298). (less)
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Pathogenic
(Nov 10, 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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Invitae
Accession: SCV000832179.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change affects FUS function (PMID: 19251627, 20606625, 23577159, 24204307, 25324524). Algorithms developed to predict the effect of missense … (more)
Experimental studies have shown that this missense change affects FUS function (PMID: 19251627, 20606625, 23577159, 24204307, 25324524). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 16222). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 19251627, 22055719; Invitae). 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 arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 521 of the FUS protein (p.Arg521Gly). This variant disrupts the p.Arg521 amino acid residue in FUS. Other variant(s) that disrupt this residue have been observed in individuals with FUS-related conditions (PMID: 20577002, 20668259, 22055719, 24908169), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 27, 2009)
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no assertion criteria provided
Method: literature only
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AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037882.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 04, 2017 |
Comment on evidence:
In affected members of a family with amyotrophic lateral sclerosis (ALS6; 608030) (Sapp et al., 2003), Kwiatkowski et al. (2009) identified a heterozygous 1561C-G transversion … (more)
In affected members of a family with amyotrophic lateral sclerosis (ALS6; 608030) (Sapp et al., 2003), Kwiatkowski et al. (2009) identified a heterozygous 1561C-G transversion in exon 15 of the FUS gene, resulting in an arg521-to-gly (R521G) substitution. Inheritance was autosomal dominant with incomplete penetrance, and the mean age at onset was 39.6 years. Affected individuals from 2 additional unrelated ALS6 families also had the heterozygous R521G mutation. The mutation was not found in 1,446 control DNA samples. (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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Genetic investigation of amyotrophic lateral sclerosis patients in south Italy: a two-decade analysis. | Ungaro C | Neurobiology of aging | 2021 | PMID: 32951934 |
FUS contributes to mTOR-dependent inhibition of translation. | Sévigny M | The Journal of biological chemistry | 2020 | PMID: 33082139 |
Chorea is a pleiotropic clinical feature of mutated fused-in-sarcoma in amyotrophic lateral sclerosis. | Flies CM | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2020 | PMID: 32116048 |
Activity-dependent FUS dysregulation disrupts synaptic homeostasis. | Sephton CF | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 25324524 |
Extensive molecular genetic survey of Taiwanese patients with amyotrophic lateral sclerosis. | Soong BW | Neurobiology of aging | 2014 | PMID: 24908169 |
An autopsy case of familial amyotrophic lateral sclerosis with FUS R521G mutation. | Mochizuki Y | Amyotrophic lateral sclerosis & frontotemporal degeneration | 2014 | PMID: 24575823 |
FUsed in sarcoma is a novel regulator of manganese superoxide dismutase gene transcription. | Dhar SK | Antioxidants & redox signaling | 2014 | PMID: 23834335 |
ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. | Zhou Y | PLoS genetics | 2013 | PMID: 24204307 |
Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq. | van Blitterswijk M | PloS one | 2013 | PMID: 23577159 |
De novo FUS gene mutations are associated with juvenile-onset sporadic amyotrophic lateral sclerosis in China. | Zou ZY | Neurobiology of aging | 2013 | PMID: 23046859 |
SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: a United States clinical testing lab experience. | Brown JA | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases | 2012 | PMID: 22292843 |
FUS mutations in sporadic amyotrophic lateral sclerosis: clinical and genetic analysis. | Sproviero W | Neurobiology of aging | 2012 | PMID: 22055719 |
Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. | Tradewell ML | Human molecular genetics | 2012 | PMID: 21965298 |
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 |
Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. | Gal J | Neurobiology of aging | 2011 | PMID: 20674093 |
Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. | Bosco DA | Human molecular genetics | 2010 | PMID: 20699327 |
Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. | Yan J | Neurology | 2010 | PMID: 20668259 |
ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. | Dormann D | The EMBO journal | 2010 | PMID: 20606625 |
SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. | Millecamps S | Journal of medical genetics | 2010 | PMID: 20577002 |
Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort. | Ticozzi N | Neurology | 2009 | PMID: 19741215 |
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 |
Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. | Sapp PC | American journal of human genetics | 2003 | PMID: 12858291 |
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Text-mined citations for rs121909668 ...
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.