NM_004960.4(FUS):c.1561C>G (p.Arg521Gly) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000703284.8

Allele description [Variation Report for NM_004960.4(FUS):c.1561C>G (p.Arg521Gly)]

NM_004960.4(FUS):c.1561C>G (p.Arg521Gly)

Gene:

FUS:FUS RNA binding protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p11.2

Genomic location:

Preferred name:

NM_004960.4(FUS):c.1561C>G (p.Arg521Gly)

HGVS:

NC_000016.10:g.31191418C>G
NG_012889.2:g.16287C>G
NM_001170634.1:c.1558C>G
NM_001170937.1:c.1549C>G
NM_004960.4:c.1561C>GMANE SELECT
NP_001164105.1:p.Arg520Gly
NP_001164408.1:p.Arg517Gly
NP_004951.1:p.Arg521Gly
NP_004951.1:p.Arg521Gly
LRG_655t1:c.1561C>G
LRG_655:g.16287C>G
LRG_655p1:p.Arg521Gly
NC_000016.9:g.31202739C>G
NM_004960.3:c.1561C>G
NR_028388.2:n.1631C>G
P35637:p.Arg521Gly

Protein change:

R517G; ARG521GLY

Links:

UniProtKB: P35637#VAR_054844; OMIM: 137070.0002; dbSNP: rs121909668

NCBI 1000 Genomes Browser:

rs121909668

Molecular consequence:

NM_001170634.1:c.1558C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001170937.1:c.1549C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004960.4:c.1561C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_028388.2:n.1631C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 6
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA; Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia; FUS-Related Amyotrophic Laterial Sclerosis
Identifiers:: MONDO: MONDO:0011951; MedGen: C2931786; Orphanet: 275872; Orphanet: 803; OMIM: 608030

Name:: Tremor, hereditary essential, 4 (ETM4)
Identifiers:: MONDO: MONDO:0013888; MedGen: C3539195; OMIM: 614782

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000832179	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20606625, 23577159, 24204307, 25324524, 19251627, 20577002, 20668259, 22055719, 24908169, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000832179

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 10, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import.

Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C.

EMBO J. 2010 Aug 18;29(16):2841-57. doi: 10.1038/emboj.2010.143. Epub 2010 Jul 6.

PubMed [citation]

PMID:: 20606625
PMCID:: PMC2924641

Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq.

van Blitterswijk M, Wang ET, Friedman BA, Keagle PJ, Lowe P, Leclerc AL, van den Berg LH, Housman DE, Veldink JH, Landers JE.

PLoS One. 2013;8(4):e60788. doi: 10.1371/journal.pone.0060788. Epub 2013 Apr 8.

PubMed [citation]

PMID:: 23577159
PMCID:: PMC3620060

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000832179.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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