16-31191418-C-G

Variant names:

• chr16-31191418-C-G
• rs121909668
• NM_004960.4:c.1561C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_004960.4(FUS):​c.1561C>G​(p.Arg521Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FUS NM_004960.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.83
• Publications: 388 publications found

Genes affected

FUS (HGNC:4010): (FUS RNA binding protein) This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]

FUS Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• amyotrophic lateral sclerosis type 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor, hereditary essential, 4

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_004960.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-31191419-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 873232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 16-31191418-C-G is Pathogenic according to our data. Variant chr16-31191418-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.1561C>G	p.Arg521Gly	missense_variant	Exon 15 of 15	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.1561C>G	p.Arg521Gly	missense_variant	Exon 15 of 15	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 07, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FUS: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting

FUS-related disorder Pathogenic:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FUS c.1561C>G variant is predicted to result in the amino acid substitution p.Arg521Gly. This variant was reported in several unrelated individuals with amyotrophic lateral sclerosis (ALS, Kwiatkowski et al. 2009. PubMed ID: 19251627; Yan et al. 2010. PubMed ID: 20668259; Ungaro et al. 2020. PubMed ID: 32951934). 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). 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). A mouse model of the p.Arg521Gly resulted in severe motor deficits mimicking human disease (Sephton et al. 2014. PubMed ID: 25324524). It has not been reported in a large population database, indicating this variant is rare; and it has been consistently interpreted as pathogenic in the ClinVar database. Taken together, we interpret this variant as pathogenic.

Amyotrophic lateral sclerosis type 6 Pathogenic:1

Feb 27, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Pathogenic:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 16222). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FUS function (PMID: 19251627, 20606625, 23577159, 24204307, 25324524). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		2.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.037	D;D;D
Vest4		0.21
ClinPred		0.98	D
GERP RS		0.20
Varity_R		0.95
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121909668; hg19: chr16-31202739;