NM_004960.4(FUS):c.559G>A (p.Gly187Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 14, 2023
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:: RCV003808703.2

Allele description [Variation Report for NM_004960.4(FUS):c.559G>A (p.Gly187Ser)]

NM_004960.4(FUS):c.559G>A (p.Gly187Ser)

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.559G>A (p.Gly187Ser)

HGVS:

NC_000016.10:g.31184974G>A
NG_012889.2:g.9843G>A
NM_001170634.1:c.556G>A
NM_001170937.1:c.547G>A
NM_004960.4:c.559G>AMANE SELECT
NP_001164105.1:p.Gly186Ser
NP_001164408.1:p.Gly183Ser
NP_004951.1:p.Gly187Ser
NP_004951.1:p.Gly187Ser
LRG_655t1:c.559G>A
LRG_655:g.9843G>A
LRG_655p1:p.Gly187Ser
NC_000016.9:g.31196295G>A
NM_004960.3:c.559G>A
NR_028388.2:n.664G>A

Protein change:

G183S

Molecular consequence:

NM_001170634.1:c.556G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001170937.1:c.547G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004960.4:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_028388.2:n.664G>A - 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
SCV004595664	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31630970, 20544928, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004595664

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 14, 2023)

germline

clinical testing

PubMed (3)
[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

Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations.

Niaki AG, Sarkar J, Cai X, Rhine K, Vidaurre V, Guy B, Hurst M, Lee JC, Koh HR, Guo L, Fare CM, Shorter J, Myong S.

Mol Cell. 2020 Jan 2;77(1):82-94.e4. doi: 10.1016/j.molcel.2019.09.022. Epub 2019 Oct 17.

PubMed [citation]

PMID:: 31630970
PMCID:: PMC6943187

Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis.

Rademakers R, Stewart H, Dejesus-Hernandez M, Krieger C, Graff-Radford N, Fabros M, Briemberg H, Cashman N, Eisen A, Mackenzie IR.

Muscle Nerve. 2010 Aug;42(2):170-6. doi: 10.1002/mus.21665.

PubMed [citation]

PMID:: 20544928
PMCID:: PMC2969843

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004595664.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects FUS function (PMID: 31630970). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 20544928). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 187 of the FUS protein (p.Gly187Ser). This variant is present in population databases (rs370954028, gnomAD 0.003%).

#	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: Sep 29, 2024

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